JPH02178287A - Optically active benzooxazine and benzothiazine, and stereoselective preparation thereof - Google Patents

Abstract

NEW MATERIAL: (R)- or (S)-7-Fluoro-8-X-3,4-dihydro-2H-[1,4]benzoxazine and benzothiazine of formula I [wherein one of R¹-R⁴ is CH₂OH, CH₂Z (wherein Z is H, F, etc.), and the others are each H; Y is O, S; X is F, methyl; etc., provided that in case of both R³ and R⁴ of benzoxazine being H, X is methyl, H].

EXAMPLE: (R)-7,8-Difluoro-3,4-dihydro-3-hydroxymethyl-2H-[1,4]benzoxazine.

USE: A starting compound for pyridobenzoxazine and pyrido-benzothiazine containing antibacterial quinolines. Optically highly pure and inexpensive.

PREPARATION: A compound of formula II (wherein one of R⁵, R⁶ is H and the other is OH; X¹ is F, Cl) is reacted with a hydroxyl group-activating agent and after the hydroxyl group is substituted with an eliminable group, the substituted compound is reacted with a reducing agent to obtain an aniline derivative. Then, this derivative is ring-opened and its 8-F atom is substituted with CH₃ or H and further the hydroxyl-protective group of CH₂Z group is eliminated.

COPYRIGHT: (C)1990,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to optically active benzoxazines and optically active benzothiazines, processes for their production, optically active pyridobenzoxazines and their use in the production of pyridobenzothiazines, and these pyridobenzoxazines. and a pharmaceutical composition comprising pyridobenzothiazine.

Quinolones are a recently developed group of antibacterial agents that are effective against both Durham-negative and Durham-positive microorganisms. Few of the quinolones synthesized to date have an asymmetric center. Some compounds of the special group of quinolones, characterized by a pyridobenzoxazine ring system, have only one methyl group at the 3-position of the oxazine ring.

These compounds therefore have an asymmetric center, (R)-
and (S)- expressed as a pair of stereoisomers. Ofloxacin is an example of this group, but until recently it has been used only as a racemic mixture of compatible isomers.

It is known that many biologically active compounds exist as mixtures of stereoisomers. Until now, these mixtures are often used as such for medicinal purposes.

Since the biological activity that is usually bundled exists primarily in one stereoisomer, the potency of the mixture appears to be reduced by about half.

However, the main reason for continuing to use mixtures of stereoisomers is that the benefit of possible increased activity does not outweigh the cost of separating the stereoisomers.

For example, the (S)-(-)-isomer of 6,7-sihydro-5,8-dimethyl-9-fluoro-1-oxo-IH,5H-benzo(ij]quinolidine-2-carboxylic acid is
While possessing strong antibacterial activity in vitro, (R)-(
It has recently been disclosed that the +)-isomer was much less active (J, F. Gerster et al., Proceedings of the 25th Intersectional Conference on Antimicrobial Agents and Chemotherapy, Minneapolis, U.S. , A. , 1985
(2010, p. 114). (S)-(-)-ofloxacin is 8 to 128 lower than (R)-(+)-ofloxacin.
It has been reported that the activity is high (I.

Hayakawa et al., Antimicrobial Agents Chemotherapy, 1986, vol. 29, p. 163).

Racemic mixtures may be resolved by known methods, such as fractional crystallization of appropriate salts or enzymatic hydrolysis of appropriate esters or amides.

The following methods have been utilized for the resolution of racemic ofloxacin: 1. Intermediates, such as racemic 9.10-difluoro-
3. Ethyl 2,3-dihydro-3-hydroxymethyl-7-oxo-7H-pyrido(1,2,3-de][1,4)benzoxazine-6-carboxylate. Resolution of 5-dinitrobenzoyl ester by high performance liquid chromatography (1, Hayakawa et al., Antimicrovial Agents Chemotherapy, 1986, Vol. 29, No. 16)
page 3) and conversion of the obtained (S)-isomer to (S)-ofloxacin by known methods.

This method, however, is not suitable for the separation of large amounts of the optically active isomers. A more suitable method is: 2. Intermediate racemic 3-acetoxymethyl-7
,8-difluoro-3,4-dihydro-2H-(1,4
] Enzymatic resolution of benzoxazines (K, Sakano et al., Agricultural Biological Chemistry, 1
987, vol. 51, p. 1265) and the obtained (S)
- Conversion of the isomer to (S)-ofloxacin by known methods.

3. Racemic intermediate 7,8-difluoro-3,
4-dihydro-3-methyl-2H-(1゜4]benzoxazine N-p-)luenesulfonyl-(L)
- Preparation of prolinylamide, crystallization and column chromatography of (R)-(+)- and (S)-(-
) - Separation of isomers (3, Atarashi et al., Chemical Pharmacy Neatical Prefecture, 1987, Vol. 55, No. 18
96) and conversion of the obtained (S)-isomer to S-ofloxacin by known methods.

4. DE-A-3639465 is a method for resolving a racemic quinolone structure containing ofloxacin, including the introduction of a hydrazinium group, the conversion of the molecule into the betaine form, and the formation of a mixture of diastereomeric salts with an optically active organic acid. Methods including manufacturing are described. Both salts are separated by crystallization, then deacidized and finally reduced to the original but optically pure form of the compound.

5, EP-A-0304684 discloses yet another method for the optical resolution of racemic benzoxazines having an asymmetric carbon atom in the 3-position. For this purpose, optically active salts are made with (R)-(-)-camphor-10-sulfonic acid. Unwanted isomers are racemized and introduced into a new resolution cycle.

A disadvantage of the process is that only up to 50% of the raw material is initially recovered as the desired product. Furthermore, additional steps are required to produce and conjugate these optically active derivatives which can be subjected to conventional separation methods.

According to EP-A-0273399, benzoxazines are prepared by stereoselective reduction of the corresponding 3,4-dehydrobenzoxazines. A fairly expensive reducing agent is required. An additional drawback is that extra steps may be required for the introduction and removal of protecting groups.

No. 4,777,253 describes a method for producing optically active ofloxacin using one enantiomer of 4-oxoquinoline-3-carboxylate having an asymmetric N-1-(hydroxymethyl)ethyl substituent. After ring closure by heating with potassium hydroxide, the pyridobenzoxazine will have an asymmetric methyl group at C2.

Advantageous chirality preservation for producing an important group of optically active 7-fluoro-8-X-3,4-dihydro-2H-(1,4)benzoxazines and -benzothiazines according to the present invention at low cost. A method is found, (Y represents oxygen or sulfur, and X represents fluorine, chlorine, methyl group, or hydrogen.) Hydroxyl group-protecting groups suitable for the reaction of the present invention include, for example, trityl group, benzyl group, methoxymethyl group, -ethoxyethyl and tetrahydropyranyl groups.

The process of the present invention uses certain fluoronitrobenzenes substituted with hydroxypropoxy groups or hydroxyisopropoxy groups as starting compounds, especially 4-fluoro-3-X'-2-(hydroxy(3c)alkoxy)nitrobenzenes of formulas 1 and 2. (wherein XI means fluorine or chlorine and Z is as defined above).

Hydroxy(3c)alkoxy group means 2-hydroxypropoxy or 1-hydroxyisopropoxy group. formula! It should be noted that the stars in and ■ indicate the asymmetric center. Therefore, both compounds exist as enantiomeric (,R)- and (S)-isomers.

To obtain benzothiazines analogous to formula (1), one starts from the corresponding sulfur analogs of formulas I and (1) containing a 2-hydroxypropylthio or 1-hydroxyisopropylthio substituent.

According to the multi-step process of the invention, first the nitro groups of compounds (1) and (2) are reduced to amino groups by conventional methods, followed by, but preferably prior to, reducing, for example, the methylsulfonyloxy group which is susceptible to ring closure. Activation of the free hydroxyl group by substitution with a leaving group such as p-toluenesulfonyloxy group, bromine or a group having the formula (phenyl)3P"-0- is carried out. The reaction is carried out for example with methylsulfonylchloride. It may be carried out at temperatures ranging from 10°C to room temperature and takes only a few minutes.

Suitable amino reducing agents are hydrogen in the presence of Raney nickel, stannous chloride in ethanol or hydrogen chloride and tin metal. If compounds not containing sulfide groups are present, palladium or platinum catalyzed hydrogenation could also be carried out; ethanol and toluene are suitable solvents. Hydrogen gas may be replaced with ammonium formate.

The reduction is carried out at room temperature and is completed within 15 minutes to 5 hours. The resulting activated hydroxyl-bearing aniline is subsequently treated with a base, such as potassium tert-butoxide or an alkali metal hydroxide salt, but preferably potassium hydroxide and more preferably +N (Ca Hs).
*-By treating with potassium carbonate and hydroxide in the presence of a phase transfer catalyst such as H2O2, the ring is closed to obtain the desired benzoxazine of formula (1) (wherein X, Y and RI, -R4 (represents the previously defined). The use of potassium hydroxide as base, preferably in combination with potassium carbonate, is particularly advantageous since high yields of benzoxazines are obtained with relatively small amounts of by-products. Suitable solvents for the ring closure reaction are found in the group of polar organic solvents such as methylene chloride. Preferably, toluene is used. The reaction takes 0.5-5 hours when carried out at -10°C to room temperature.

The above-mentioned hydroxyl group activation and subsequent ring closure of the hydroxy(3c)alkoxyaniline may be carried out as a step in the same vessel, preferably using toluene as a solvent.

The corresponding benzothiazine is obtained by a reaction sequence similar to that described above, but starting from the corresponding sulfur analog.

Compounds ■ in which X represents hydrogen or methyl group are new substances, and they differ from the corresponding compounds in which X represents fluorine,
Metals such as dimethylcopper lithium by methods known in the art, for example reduction with sodium hydride in dimethylformamide at temperatures ranging from room temperature to reflux temperature, respectively, or in a suitable solvent such as diethyl ether or tetrahydrofuran. It may also be produced by methylation with an organic compound under similar reaction conditions.

3-CH from the raw material compound ■ that has a propoxy substituent
2Z-benzoxazine is obtained, whereas 2-CH*Z-benzoxazine is obtained from compound (1) having an isopropoxy substituent. 3-CHx Z-benzoxazine and the corresponding 2-10 Hg Z-benzoxazine are regioisomers of each other.
r). Both seem to be formed during the same reaction from the mixture of (1) and (2) obtained in the previous step.

Compounds 1 and 2 both have asymmetric centers indicated by asterisks. Although the production of benzoxazine 2 can be carried out in racemic mixtures, it is preferable that the stereochemically pure starting compound 1 or 2 is used. In that case, the reaction proceeds without substantial or any racemization, resulting in a stereochemically pure or substantially pure benzoxazine.

The reaction of the present invention therefore provides a method for synthesizing CHtOH- or CH2Z-1:substituted benzoxazines (and corresponding benzothiazines) with the desired stereochemical configuration.

For the production of the above-mentioned starting compounds I and (2), if it is required that they be in optically active form, the present invention can be used to prepare some nearly chiral compounds starting from commercially available and, if necessary, optically active compounds. Table I provides a survey of the reactants of methods a-j that provide properties-preserving reactions. In the compounds (1) and (H) exemplified above, Z represents hydrogen, but the method is also effective for compounds where Z represents fluorine or a protected hydroxyl group: (R)-4-fluoro-3-halo-2-(2-
Hydroxypropoxy)nitrobenzene (1) is obtained together with its regioisomer (R)-4-fluoro-3-halo-2-(1-hydroxyisopropoxy)nitrobenzene (n), where halo represents fluorine or chlorine. , the molar ratio is about 60/40 to about 70/30).

When starting from the corresponding (S)-1,2-propanediol, both corresponding (S)-products are formed in similar molar ratios. When (R)- or (S)-2-hydroxypropanethiol is used, (R)- and (S)-4-fluoro-3-halo-2-(2-hydroxypropylthio)nitrobenzene are formed, respectively. However, their regioisomers cannot.

Appropriate base conditions include (1-4C) alkoxides of lithium, sodium or potassium, (1-40) alkyllithium compounds such as butyllithium, alkali hydrides such as sodium hydride, or tertiary amines such as triethylamine. It will be done. Suitable solvents are tetrahydrofuran or toluene. The reaction is preferably carried out between room temperature and reflux temperature.

Since the chirality of the compound is preserved during this manufacturing process, if a pure optically active starting compound is used in this case,
It is noteworthy that a stereochemically pure product is obtained.

b. Reacting 3-fluoro-2-halo-6-nitrophenol with either (R)- or (S)-2-methyloxirane in the presence of a base (where halo represents fluorine or chlorine), (R)- or (S)-4-fluoro-3-halo-2-(2-hydroxypropoxy)
- Nitrobenzene (1) together with their regioisomer (R)- or (S)-4-fluoro-3-halo-2-(1-hydroxyisopropoxy)nitrobenzene (II) at a concentration of about 60/40 Approximately 70/
Obtained in a molar ratio of 30.

As indicated by (R) and (S), which represent chirality, this reaction proceeded while maintaining chirality.

Along with the (R)- or (S)-oxirane, 3-
When using fluoro-2-halo-6-nitrothiophenol, (R)- or (S)-4-fluoro-3
-Halo-2-(2-hydroxypropylthio)nitrobenzenes are formed, but their regioisomers are not. Although some bases are suitable, such as ethyldiisopropylamine, inorganic bases are preferably used because they exhibit less racemization. Suitable inorganic bases are lithium hydroxide, sodium hydroxide and potassium hydroxide. The reaction should be carried out in a sufficiently polar solvent, such as ethanol, although tetrahydrofuran is also a suitable solvent. Preferably the reaction temperature is between room temperature and 1
50°C, more preferably the boiling point of the solvent. The sulfur analog reacts already at room temperature.

0.3-Fluoro-2-halo-6-nitrophenol is prepared from (R)- or (S) in the presence of an inorganic or organic base.
)-1-L-2-propanol (L means an easily leaving atom or group such as bromine, iodine or tosylic acid, and halo is as defined above)
, (R)- or (S)-4-fluoro-3-halo-
2-(2-hydroxypropoxy)nitrobenzene (1
) is its regioisomer (R)- or (S
)-4-fluoro-3-halo-2-(1-hydroxyisopropoxy)-nitrobenzene (n), together with about 6
A molar ratio of 0/40 to about 70/30 is obtained.

As indicated by (R) and (S), which represent chirality, this reaction proceeded while maintaining chirality.

(R)- or (S) when using 3-fluoro-2-halo-6-nitrothiophenol with either (R)- or (S)-1-L-2-propanol.
-4-fluoro-3-halo-2-(2-hydroxypropylthio)nitrobenzene is formed, but its regioisomer is not. A suitable inorganic base is, for example, potassium carbonate, but other bases of potassium, sodium or lithium such as hydroxide may also be used. The reaction is carried out in a polar solvent, for example dimethylformamide. Good results are also obtained with organic bases such as ethyldiisopropylamine or triethylamine when used in combination with solvents such as tetrahydrofuran or dioxane. The reaction temperature is between room temperature and reflux temperature, preferably 1
The temperature is below 00℃.

A mixture of d,3-fluoro-2-halo-6-nitrophenol and (R)- or (S)-1,2-propanediol is treated with diethyl azodicarboxylate in the presence of an activating agent such as triphenylphosphine. (R)- or (S)-4-fluoro-3 by reacting with a dialkyl azodicarboxylate such as
-Halo-2-(2-hydroxypropoxy)nitrobenzene (I), each of its regioisomers (S
)- or (R)-4-fluoro-3-halo-2-(
1-Hydroxyisopropoxy)nitrobenzene (If
).

When 3-fluoro-2-halo-6-nitrothiophenol is used with either (R)- or (S)-1,2-propanediol, (R)- or (S)-4-fluoro -3-halo-2-(2-hydroxypropylthio)nitrobenzene are their regioisomers (S)- or (R)-4 respectively
-Fluoro-3-halo-2-(1-hydroxyisopropylthio)nitrobenzene.

Although several fully polar solvents can be used, tetrahydrofuran is the preferred solvent.

It should be noted that in this case, if a pure optically active starting compound is used, a stereochemically pure product will be obtained, since the chirality of the compound is preserved during this manufacturing process.

The reactions described give rise to mixtures of regioisomers, each of which is in stereochemically pure form, with the proviso that the optical purity may vary depending on the nature of reactant 2 specified in Table I. The separation of intermediate regioisomers may, however, be postponed. The mixture is then used in the subsequent benzoxazine synthesis to yield a mixture of 3-methylbenzoxazine and the corresponding 2-methylbenzoxazine, which can be easily separated by conventional physical methods such as column chromatography. I think you can.

However, in the following method for producing 4-fluoro-3-halo-2-(hydroxy(3c)alkoxy)nitrobenzene of formula (1) or H (e, -j, ), no regioisomer is formed and the ionic isomer is not formed. C1 is preferred because it contributes considerably to the economic efficiency of the process.

e, 3-fluoro-2-halo-6-nitrophenol and (R)- or (S)-2-OR'-propanol (wherein R' represents a hydroxyl protecting group as exemplified above) is reacted at room temperature in the presence of an activator such as triphenylphosphine in combination with a dialkyl azodicarboxylate such as diethyl azodicarboxylate (Mitsunobu reaction), for example DOWEX 50W-
After removing the protecting groups under weakly acidic conditions using an acidic ion exchange resin such as X8-400H” (RTM), each (
R)- or (S)-4-fluoro-3-halo-2-
(2-Hydroxypropoxy)nitrobenzene (1) is obtained, but its regioisomer is not expressed in a more acidic environment.

0■ (e) =IO-CHg CH-CHzZ舊OR'' When using 3-fluoro-2-hero-6-nitrothiophenol with (R)- or (S)-2-OR'-propanol , respectively (R)- or (S)
-4-fluoro-3-halo-2-(2-hydroxypropylthio)nitrobenzene is formed, but again no regioisomers are possible. Although any sufficiently polar solvent may be used, tetrahydrofuran is the preferred solvent.

It should be noted that in this case, if a pure optically active starting compound is used, a stereochemically pure product will be obtained, since the chirality of the compound is preserved during this manufacturing process.

To obtain the regioisomers of the products f, e, 3-fluoro-2-halo-6-nitrophenol and (R)-
or (S)-1-(OR')-2-propanol (
However, R# indicates a hydroxyl protecting group as exemplified above)
are reacted at room temperature in the presence of an activating agent such as triphenylphosphine in combination with a dialkyl azodicarboxylate such as diethyl azodicarboxylate, and the protecting group is removed under suitable known conditions. After that, (S)- or (R)-4-fluoro-3-halo-2-(1-hydroxyisopropoxy)-nitrobenzene (I) is obtained, respectively, but not its regioisomer.

nt+ When using 3-fluoro-2-halo-6-nitrothiophenol together with (R)- or (S)-1-OR"-2-propanol, (S)- or (
R)-4-fluoro-3-halo-2-(1-hydroxyisopropylthio)nitrobenzene is formed, but again no regioisomers are possible.

(Although some polar solvents may be used, tetrahydrofuran is the preferred solvent.

It should be noted that in this case, if a pure optically active starting compound is used, a stereochemically pure product will be obtained, since the chirality of the compound is preserved during this manufacturing process.

g,3-fluoro-2-halo-6-nitrophenol can be converted to (R)- or (S) in the presence of an inorganic or organic base.
)-1-L-2-OR'-propane (wherein, L and halo are as defined for C9, and R' is a hydroxyl-protecting group that is stable in the phenol environment, as exemplified above) (R)- or (S)-4- after removing the protecting group under suitable known conditions.
Fluoro-3-halo-2-(2-hydroxypropoxy)-nitrobenzene (1) is obtained, but not its regioisomer.

(gl = L-C1lt CH-CIIzZ0R
'(R)- or (S)-1-L-2-OR' When using 3-fluoro-2-halo-6-nitrothiophenol with either propane, (R)- or (S) -4-fluoro-3-halo-2-(2-hydroxypropylthio)nitrobenzene is formed, but again no regioisomers are possible.

The preferred base is ethyldiisopropylamine, used in dimethylformamide, preferably at 80-100°C, although other tertiary amines and inorganic bases of sodium, potassium and lithium may also be used.

Although several scratchy solvents may be used, dimethylformamide is the preferred solvent.

To obtain regioisomers of the products h, g, 3-fluoro-2-halo-6-nitrophenol is converted to (R)- or (S)-2- in the presence of an inorganic or organic base.
L-1-OR'-propane (L and halo are as defined for C0, R' is a hydroxyl protecting group as exemplified above) and reacted under appropriate known conditions. After removing the protecting group with , (S)- or (R)-4-fluoro-3-halo-2-(1-hydroxyisopropoxy)-nitrobenzene (11) is obtained, respectively. Regioisomers cannot.

When using 3-fluoro-2-halo-6-nitrothiophenol with either R)- or (S)-2-L-1-OR' propane, each (S)-
or (R)-4-fluoro-3-halo-2- <1
-hydroxyisopropylthio)nitrobenzene is formed, but again no regioisomers are possible.

Preferred reaction conditions regarding base and solvent are g.

As stated in.

i. The most preferred method, however, is a.

As described in 2.4-difluoro-3-halonitrobenzene, it is reacted with (R) to (S)-2- at a temperature between room temperature and reflux temperature.
OR'-propanol (as exemplified above, R# indicates a hydroxyl protecting group, and halo indicates fluorine or chlorine) under basic conditions, and the protecting group is removed under appropriate known conditions. After removal of (R)- or (S)-4-fluoro-3-halo-2-(2-hydroxypropoxy)nitrobenzene (1), respectively, but not the regioisomer.

0■ (1)"80 CHt-CI-CIIzZ嘗OR' When using (R)- or (S)-2-OR'-propanethol, (R)- or (S)-4-fluoro-3 -halo-2-(2-hydroxypropylthio)
Obtain nitrobenzene.

Appropriate base conditions are as exemplified in a.

Very good results are obtained using inexpensive inorganic bases such as potassium hydroxide or potassium carbonate, preferably a mixture of both, with yields of over 90%. ”N(C4Hs
) Phase transfer catalysts such as s-H2O2 seem to be effective. Suitable solvents are tetrahydrofuran and preferably toluene, but other solvents may also be used. Removal of the hydroxyl protecting group can be accomplished, for example, by subjecting a solution of the protected compound in methanol to DOWEX 50W-X8-400H''' (RT
This can be carried out by contacting with a strongly acidic ion exchange resin such as M).

It is worth noting that the present method is most advantageous in the preparation of stereochemically pure products starting from pure optically active propatool derivatives, since the chirality of the compound is preserved during the preparation process. It is.

Similar to the method of j, i, the regioisomer of the compound of i, i.e. (R)- or (S)-4-fluoro-3-halo-2-(1-hydroxyisopropoxy)nitrobenzene (n) using (R)- or (S)-t-OR'-2-propanol, respectively,
Available on a limited basis.

When using the corresponding thiol (method i, class i), (R)- or (S)-4-fluoro-3-halo-
2-(1-hydroxyisopropylthio)nitrobenzene is obtained.

It should be noted that when using 2,4-difluoro-3-halonitrobenzene as the starting compound in methods i and j, 4-fluoro substitution occurs only in a very small amount, if at all. It is. This selectivity further contributes to the economy of the method.

The methods described in a.
(However, Z represents fluorine or a protected hydroxyl group) and the compound listed in Reactant 2 of Table 1 as a raw material compound (However, Z represents fluorine or a protected hydroxyl group, and R" represents a hydroxyl group-protected compound. , L denoting a leaving group as exemplified above).If the reaction provides a mixture of regioisomers, their proportions are particularly suitable for preparing oxiranes, such as The use, if any, depends on the electronegativity of Z. The results of various raw compound preparation methods with respect to preservation of chirality and expression of regioisomers are summarized in Table I.

From the obtained Z-substituted compounds, optically active substances 2-CH2Z- and 3-
CH2Z-benzoxazine and the corresponding benzothiazine are obtained.

(R)- and (S)-7-fluoro-8-X of general formula
-3,4-dil:,)'o-2H-(1,4]benzoxazine (However, one of the substituents R'-R' is CH2
0H or CH2Z, the others are hydrogen, Z represents hydrogen, a fluorine group or a protected hydroxyl group, and X represents fluorine, chlorine, a methyl group or hydrogen, provided that benzene in which both R3 and R4 represent hydrogen In oxazine, X represents a methyl group or hydrogen) and the corresponding benzothiazine are new compounds.

The optically active substituted benzoxazines and benzothiazines produced by the present invention are useful compounds. Representative compounds of this group serve as starting compounds in known processes for producing pyridobenzoxazines and pyridobenzothiazines, including important antimicrobial quinolines such as (S)-ofloxacin (formula 1).

Previous techniques suitable for the production of pyridobenzoxazines and pyridobenzothiazines often employ racemic starting compounds, making a resolution step unavoidable when optically active end products are desired. In contrast,
The method is relatively inexpensive and uses starting compounds that are themselves already optically pure or at least substantially pure and remain pure in subsequent steps where their chirality is preserved in known methods. The present invention provides a method without an expensive splitting step. In the most preferred embodiments, no more than 2% of other stereoisomers will be detectable in the resulting product.

According to another aspect of the invention, therefore, the optical activity and lidobenzoxazines and pyridobenzothiazines obtained according to the invention are characterized in particular by the stereochemical configuration necessary to obtain the desired optically active end product. It is prepared from benzoxazine and benzothiazine by methods known per se.

These products are (R)- and (S)-10-A-9-fluoro-2,3-dihydro-2(or 3)-CH
! Z-7-oxo-7H-pyrido (1,2,3-de)
It belongs to the group of (1,4) benzoxazine-6-carboxylic acids and the corresponding sulfur analogues, which group is represented by the formula (1).

(In the formula, one of R1, RZ, R'l<&;!R' represents CH2Z or CH, OH, and the other R's represent hydrogen. A represents X or NQ'Q" However, X, Y and Z are as defined above, and Ql
and Q! are the same or different, and hydrogen or (
1-6G) represents either an alkyl group (however, both Ql and Qt do not represent hydrogen), or both Ql and Q2 contain l or 2 nitrogen ring atoms and/or Contains one oxygen ring atom, (1-4
C) May be substituted by an alkyl group (3-7
0) forming a heterocycle). Suitable heterocycles are piperazine, 1-methylpiperazine, pyrrolidine, 2- or 3-methylpyrrolidine and imidazole.

A and RI Ra are as defined above, with the proviso that in pyridobenzoxazines in which R'' and R4 both represent hydrogen, compounds of formula V in which A represents a methyl group or hydrogen are new compounds.

Processes known in the art suitable for preparing these compounds from the penzoxazine and benzothiazine obtained according to the present invention include the following steps: a.
1-6C) Reaction with alkyl (preferably diethyl) ethoxymethylene malonate, b followed by ring closure in the presence of an acid, C1 Hydrolysis of the resulting ethyl ester of formula 1 NHQ'
Any substitution by Q”.

If 10-chloro-pyridobenzothiazine is substituted, the sulfur should first be oxidized to the sulfoxide or sulfone and reduced again after the substitution reaction.

The compounds showing surprising antibacterial activity as shown in Table ■ belong to the novel pyridobenzothiazines produced by the present invention.
Its activity is comparable to or slightly inferior to that of ofloxacin. They have the added advantage of not being able to cross the blood-brain barrier.

(In the formula, R', R', R', R', X and ye
t is as defined above for the corresponding carboxylic acid), d, amine GBR2379 where Ql and Q2 of the 10-fluorine atom of the obtained carboxylic acid are as defined above.
0 is (S)-ofloxacin (S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido (
1,2゜3-de) (1,4) Benzothiazine-6
-Carboxylic acid whose intracyclic oxygen pressure is replaced by an intracyclic sulfur atom.

MIC = Minimum inhibitory concentration (■/1) MBC = Minimum bactericidal concentration (mg/1) Each assay is 2
I did it one time at a time.

Racemic GBR23790 is known from E PO 165375 (compound history in Table 1). Its MIC values for bacteria 1.2 and 4 in Table 1 above are 0.78, 0.78 and 50, respectively.

The racemic material is apparently much less potent.

According to yet another aspect of the present invention, the formula V obtained with the present invention
Therapeutically useful representatives of pyridobenzoxazines or the corresponding pyridobenzothiazines, particularly the optically active (S)-ofloxacin and its pharmaceutically acceptable salts, are used in antimicrobial applications in the preparation of pharmaceutical compositions. Used in effective amounts.

Although these compounds can be administered alone, they will ordinarily be administered in a mixture with a pharmaceutically acceptable diluent or carrier selected for the indicated route of administration and standard pharmaceutical practice. For example, they may be either in the form of tablets containing excipients such as starch or lactose, or capsules, alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Can be administered orally. The compounds can be included in compositions suitable for parenteral, intramuscular, intravenous or subcutaneous administration. For parenteral administration, they are best used in the form of sterile aqueous solutions which may contain other solutes, such as sufficient salt or glucose to make the solution isotonic.

The following examples are given by way of illustration and should not be construed as limiting the invention.

Normally, the NMR spectrum is Prutzka-AM 360MHz.
Measured with a spectrophotometer. Prutska-AM60 depending on the case
A 0M11z spectrophotometer was used.

(R)-2,2,2-1-lifluoro-1-(9-anthryl)ethanol was introduced preferably at 253° for NMR spectroscopy of optical purity.

The optically active (3c)-raw material compound is prepared from (R)-butyl lactate, (S)-ethyl lactate and (R)-2,3-isopropylidenedioxy-1-propanol (R-turketal) using a well-known method. Manufactured using (R)- and (S)-propylene oxide and (R)-2,3-
Isopropylidene dioxy-1-propanol was also used as received.

All of these compounds were available for purchase.

Typically, reactions were carried out under dry N2 bubbling.

Regarding nomenclature, we have introduced a substituted isopropoxy group, which is another name for substituted l-methylethoxy group. For example, the name 3,4-difluoro-2-(1-hydroxyisopropoxy)nitrobenzene is used for 3,4-difluoro-2-(2-hydroxy-1-methylethoxy)nitrobenzene.

Example 1 A solution of 11.4 g of (R)-1,2-propanediol in 50 LIII of tetrahydrofuran was added to a suspension of 1.8 g of sodium hydride in 75 ml of tetrahydrofuran under stirring at 0°C. . An oily precipitate of sodium salt formed. After stirring for 20 minutes, the reaction mixture was cooled to -40°C and a solution of 13.28 g of 2,3.4-trifluoronitrobenzene in 75 ml of tetrahydrofuran was added.

After reacting for 1 hour at −40° C. and 1 hour at 0° C., the reaction mixture was evaporated to dryness, the residue was dissolved in diethyl ether, and the solution was washed with water. The ether layer was dried over anhydrous sodium sulfate, filtered, and then evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solution: Nidiethyl ether/hexane: 1/1). The product, 10.3 g of oil, is a 3:2 mixture of the title compound.
It turned out to be a mixture.

Yield: 59%. The mixture has [α] = +28.8° (
C=2, CHCj2s) and was used as is in Example 2.

'HN? JR (CDCj!,, ppm) Main compound: Delta = 1.26 (6,3H), 2.66 (br, s
, IH), 4.11 and 4.39 (2x m,
2H), 4゜23(m, IH), 7.02
(m, IH).

7.74 (m, IH).

Sub-compound: delta=1.40 (d, 3H), 2.
66 (br, s.

IH), 3.80 (m, 2H), 4.7Nm
, 1N), 7.02 (m.

IH), 7.72 (m, IH).

Example 2 To a solution of 14.67 g of the mixture described in Example 1 in 250 ml of anhydrous diethyl ether, 12.0 I1
11 of triethylamine was added. 75ml for light mixture
7.44 g of methanesulfonyl chloride in anhydrous diethyl ether were mixed dropwise with stirring while maintaining the temperature between 15 and 20°C.

After stirring for 0.5 h, the conversion was complete as evidenced by TLC on silica gel (hexane/diethyl ether: 2/3) and water was added.

The organic layer was separated, washed five times with water, and dried over anhydrous sodium sulfate.

The organic solution was then filtered and evaporated under reduced pressure to yield 19.3 g of a 3=2 mixture of the title compound. Yield: 98.5%.

This mesylate mixture was used as is in Example 3.

21゛To a solution of 18.7 g of the mixture prepared in Example 2 in 60111 absolute ethanol, 3 g of 10% Pd/C was added.
was added and the mixture was stirred at 20-25°C and saturated with H2. After the required amount of H2 was absorbed, the reaction mixture was filtered through Hyflo (RTM) and the filtrate was concentrated. The residue was dissolved in diethyl ether, the ether solution was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure.

Yield was 16.3 g of a 3=2 mixture of the title compound (96%). The 5 mixture was used as is in Example 4.

16.02 g of the mixture prepared in Oxazine Example 3 was added to 500 m
In a solution of II in anhydrous tetrahydrofuran, 14
, 2 g of potassium tert-butoxide were added in small portions with stirring. The reaction mixture was stirred for 30 minutes, maintaining the temperature at 20-25°C. The mixture was then evaporated to dryness and the residue was dissolved in a 1:1 mixture of water and diethyl ether. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The acid oil residue (10 g) contained two products, which were separated by column chromatography on silica gel (eluent Nidiethyl ether/hexane; 1/1). The fractions containing the main product were combined and distilled to yield 3.5 g of (S)-7°8-
Difluoro-3,4-dihydro-3-methyl-2H-(
1,4) Benzoxazine was obtained. Yield: 33%, (
, 12) = -6,3° (c = 2.1, CHC
l5). The interim product was contaminated with less than 2% of the (R)-isomer.

Iris HNMR (CDC123, ppm) Del = 1.
19(d, 3H).

3.50 (Dl, IH), 3.79 and 4.28
(2x dd, IH).

6.25 (+s, III), 6.54 (m, 1
8).

The fractions containing the by-product of dihydro-2-methyl-2H-(1,43benzoxazine Example 4) were combined and evaporated to dryness to yield 2.6 g of (R)-7,8-difluoro-3,4- Dihydro-2-methyl-2H-(1°4)benzoxazine was obtained. Yield: 25%.

[α) = +37.7° (C = 2.33, CHCf
,).

The optical purity was determined by NMR spectral analysis and was 99.
It was 0% or more. The NMR spectrum was obtained from 2.
3-difluoro-6-nitrophenol at 140°C (
R)-7,8-difluoro-3,4-dihydro-2-methyl-2H-(1,4)benzoxazine prepared by conversion with R)-propylene oxide and ethyldiisopropylamine. Ta. After conventional processing, 3=2 of (R)-3,4-difluoro-2-(2-hydroxypropoxy)nitrobenzene and (R)-3,4-difluoro-2-(1-hydroxyisopropoxy)nitrobenzene A mixture was obtained. The mixture was directly mesylated, reduced, cyclized and finally separated as described in Examples 2.3 and 4.

'HN! JR (CDC1'3.2gm> Delta=1.
42(d, 3H).

3.10 and 3.36 (2X dd, 2H),
3.26 (br, s, IH).

4.28 (m, IH), 6.28 (m, 1
B), 6°54 (m, IH).

Example 6 As-made (S)-(-)-7,8 prepared in Example 4
-difluoro-3,4-dihydro-3-methyl-28-
A mixture of 2.66 g of C1,4]benzoxazine and 3.11 g of diethyl ethoxymethylene maloney was stirred under nitrogen gas and heated at 140-145° C. for 2 hours. After cooling, 20 g of ethyl polyphosphate were added and the mixture was heated again at 140-145° C. for 1 hour. After cooling, the nuclear reaction mixture was poured into ice water and extracted three times with chloroform. The collected organic layer was washed with 5% sodium carbonate solution and water.

The organic layer was dried over anhydrous sulfuric acid, filtered, and then distilled to dryness. Diethyl ether was added to the residue and the crystalline material was filtered off, washed and dried to give 3.1 g of the title product (70%). M, p.

254-255°C. [α) =-64,8° (c=
0925, acetic acid).

IHNMR (CF, C00D, ppm) delta = 1
．． 19 (tr, 3H).

1.44 (d, 3) 1), 4.38 (m, 4H
), 4.84 (m, IH).

7.75 (dd, LH), 8.97 (s, IH
).

Example 7 (S) -(-)-9,10-difluoro-2°3-dihydro-3-methyl-7-oxo-78-pyrido (1,
2,3-de) (1,4)benzoxazine-6-
3.2 g of ethyl carboxylate, 32 ml of acetic acid and 8 ml of concentrated hydrochloric acid
ml of the mixture was heated at reflux temperature for 3 hours. After cooling to 5° C., the precipitated crystals were collected by filtration and washed successively with water, ethanol and diethyl ether.

After drying, 2.64 g of the title product was obtained. Yield (c
= 1.0, DMSO).

'HNMR (CF3GOOD, ppm) delta = 1.
46(d, 38).

4.38 (ABq, 2H), 4.85 (Il,
IH), 7.75 (dd, 1ll).

9.04 (s, IH).

1.41 g of (
S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido (1,2,
7 tan of BF in a suspension of 3-de) (1,4) benzoxazine-local ponic acid.

The etherate was mixed dropwise with stirring at room temperature.

After stirring the reaction mixture for 5 hours, the precipitate was collected by suction,
Washed with diethyl ether and dried under reduced pressure.

The resulting chelate was dissolved in 15+nj7 dry dimethyl sulfoxide and 1.42 ml triethylamine and 0.8 g N-methylpiperazine were added to the solution.

The mixture was stirred at room temperature for 18 hours, and then concentrated to dryness under reduced pressure. The residue was treated with diethyl ether and methanol 4
0mj! and 1.42 mj7 of triethylamine, and the solution was heated at reflux temperature for 24 hours. After cooling, the reaction mixture was concentrated to dryness, the residue was dissolved in 50 mj' of 10% hydrochloric acid, and the solution was extracted three times with chloroform. The aqueous layer was separated, and the pH was adjusted to 11 with 4N sodium hydroxide, and then adjusted to pH 7.3 with 1N hydrochloric acid. 20% of the solution
Extracted three times with 0 ml of chloroform, the extract was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting powder was recrystallized from ethanol-diethyl ether to yield 1.0 g of the title product. Yield: 55%. M,
p, 240-245°C.

(Disassembly). [α) = -77,8° (C=0.2,
0.05N NaOH).

JL (1.15 g of (S) dissolved in 6 IIll of pyridine)
)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido (1,2,3
-de) 1.2 g of N-methylbiperazine was added to (1,4) benzoxazine-6-carboxylic acid. Next, the mixture was heated at 120° C. for 10 hours while stirring.

After cooling, post-treatment was performed as described in Example 8.

In this case, diethyl ether was added to the residue obtained by distilling off the chloroform extract layer. The crystalline material thus formed was collected by filtration, and after washing and drying, 1.3 g of crude fibrous material was obtained. 1 by recrystallization from isopropanol
．． 1 g of the title product was obtained.

Yield: 14.3%. [α)” = −78,1° (c
=0.2.0.05N NaOH) aM, p, 225
-226℃.

'HNMR (CDCj2 s, ppm) delta = 1.
62(d, 3H).

2.38 (s, 3H), 2.58 (br, s,
411), 3.41 (m, 4H).

4.44 (ABq, 2H), 4.59 (m,
1ll), 7.67(d, 11().

8.65 (inciting, IH).

(R)-(+)-7°8-difluoro-3,4-dihydro-2-methyl 2H-(1,
4) A mixture of 1.00 g of benzoxazine was reacted with 1.16 g of diethyl ethoxymethylene malonate under the conditions described in Example 6 and work-up was carried out as reported there.

1.3 g of the title product was isolated.

Yield near 8%, M, p, 254-255°C.

[α) = -88,4° (c=0.16, CHC
l5)-'HNMR (CF3cOOD, ppm,
) Delta = 1.16 (tr, 3H).

1.39 (d, 3H), 4.20 and 4.58 (
2x dd, 211).

4.33(q, 28), 4.42(+*,
LH), 7.69 (dd, 1) 1).

8.84 (5, IN).

'II NMR (CF3cOOD, ppm) delta =
1.46(d, 3H).

4.28 and 4.67 (dd, d, 28), 4.
49 (m, 1ll), 7.76 (m, IH),
8.79 (s, l1l).

2.8 g of (R)-C-”)-9,10-difluoro-
2,3-dihydro-2-methyl-f-oxo-7H-pyrido(1,2,3-de) (1,4)ethyl benzoxazine-6-carboxylate as described in Example 7 at 28 mj! of acetic acid and? +sJ! of concentrated hydrochloric acid.

After normal work-up, 2.2 g of the title product was obtained.

Yield: 87%, M, p, 278-280°C.

[α) = −56,4° (c=0.2, CHCl1.
).

10.4mj! 2.0 g of (R)-(-) in pyridine of
-9,10-difluoro-2,3-dihydro-2-methyl-7-oxo-7H-pyrido (1,2°3-da)
(1,4)benzoxazine-6-carboxylic acid and 2
．． A mixture of 1 g of N-methylbiperazine was heated to 6 ml at reflux temperature.
heated for an hour. After cooling, the reaction mixture was evaporated to dryness, water was added to the residue and the resulting crystalline product was washed with water and ethanol.

Further purification was carried out by dissolving the crude in dilute sodium hydroxide, and crystallization was induced by adding IN hydrochloric acid until pH=7.3. The crystals were collected by filtration, washed and dried to obtain 2.2 g of the title compound. Yield: 85%. M,p
, 295℃ (dec), (α] = -46,9°
(c=0.29, Q, Q5N, NaOH).

'tlN? JR (CDC13, ppm) delta = 1.
63(d, 3H).

2.49 (S, 2tl), 2.72 (br, s,
4H), 3.49 (br, s.

4H), 4°06 and 4.33 (2X dd, 2
H), 4.48 (m.

1tl), 7.72(d, IH), 8.58
(s, IH).

Example 13 7.6 g of (
S)-1,2-propanediol is added to 1,2 g of sodium hydride suspended in 50 ml of tetrahydrofuran and after metallization 8.85 g of 2,3,4-trifluoro in 25IT11 of tetrahydrofuran are added. Add nitrobenzene.

Both reaction and work-up conditions were similar to those described in Example 1.

After purification by column chromatography, 8 g of an oily product consisting of a 3=2 mixture of the title isomers were obtained. The mixture has [α) = -29,3° (c = 2.09, CHC
fi). Both isomers were found to be optically pure as confirmed by NMR.

'II NMR (CDCI!, ppm) Main compound:
Delta = 1.26 (d, 3) +), 4.12 and 4.38 (2x m, 2) 1), 4.22 (m,
IH), 7.02 (m, IH), 7.72 (
n+, 11).

Sub-compound: delta = 1.40 (d, 3H), 3.77
(m, 2H).

4.70 (m, IH), 7.02 (m, IH)
, 77-68 (+1ll).

Additionally, 1.3 g of slightly impure (S)-1°2-bis(2,3-difluoro-6-nitrophenoxy)propane was isolated.

'tl NMR (CDC12i, pPII+) delta =
1.53 (d, 3+1).

4.38 and 4.6H2x +s, 2/ll)
, 4.99 (m, IH), 7.01 (s, IH
), 7.67 (m, IH).

Oxypropoxy)nitrobenzene and (S)--P
Rouleau -- Pal Pa 200mj! 11.1 g of the mixture described in Example 13 and 9.2 mf of triethylamine in diethyl ether were treated as described in Example 2 with 5.7 g of methanesulfonyl chloride diluted with 5011 Il of diethyl ether.

After usual work-up, a 3;2 mixture of the title compound 14,3
g was isolated. Yield: 100%. The mixture is (α)
=+27.1' (c=1.64, CHCj!i
) and was used in Example 15 as it was.

'HNMR (CDCI23.ppm) Main compound: Delta = 1.53 (d, 3H), 3.07 (s, 38
), 4.38 (s, 2H).

5.13 (m, IH), 7.10 (low,
IH), 7.74 (m, 11th edition).

Sub-compound: Delta = 1.47 (d, 3H), 3.0
3(s, 3)1).

4.38 (m, 2) 1), 4.83 (m, l1l)
, 7.10(n+, IH), 7.74(s, I
H).

oxypropoxy)aniline and (S)-3,4-di
14.0 g of the mixture prepared in 14 was dissolved in 200I11 of absolute ethanol, 3 g of 10% Pd/C was added, and the mixture was stirred vigorously (do not stir). to 20-25° C. and saturated with H2.

After the required amount of H2 was absorbed, the reaction mixture was treated according to Example 3.

11.9 g of a mixture of title compounds were isolated. Yield: 9
4%. The mixture was used as is in Example 16.

10 g of oxazine and potassium tert-butoxide were added in portions with stirring to 11.24 g of the mixture prepared in Example 15.
was added to 300 mff1(7) dissolved in anhydrous tetrahydrofuran.

After work-up of Example 4, 1.5 g of the title product was obtained in optically pure form (less than 1% of the enantiomer was present in N
(detected by MR). Yield: 20%. [α) =
+6.7° (c=1.79, CHCj23).

The NMR spectrum was similar to that of Example 4.

Fractions containing by-products of Oxazine Example 16 were collected and evaporated to provide optically pure (S)- as shown by NMR spectroscopy.
7,8-difluoro-3,4-dihydro-2-methyl-
1.15 g of 2H-(1,4)benzoxazine was obtained. Yield: 15% [α)”=-38.3° (C=1.9
1, CHClz) - The NMR spectrum was equivalent to that of Example 5. The reaction was carried out according to the method described in Example 6, and for the condensation reaction 1.35 g of (R)-C1) -7゜8-difluoro-3,4-dihydro-3-methyl-2H-(1,4)
From benzoxazine and 1.58 g of diethyl ethoxymethylene malonate and 10 g for the ring closure reaction.
This was done starting from ethyl polyphosphate.

1.38 g of the title compound was obtained.

Yield: 6)%.

[α) = +67.8°C (c = 0.24, acetic acid).

'HNMR (CFsCOOD, ppm) delta = 1.
21 (tr, 3) 1).

1.47(d, 3)1), 4.4Hm, 48)
, 4.88 (m, 1tl).

7.78 (tr, IH), 9.00 (s, 1
ll).

-dihydro-3-methyl-7-oxo-7H-pi1.3
g of (R)-(+)-9,10-difluoro-2,3-
Dihydro-3-methyl-7-oxo-7H-pyrido (1
,2,3-de) (1,4)benzoxazine-6
- ethyl carboxylate, 13 ml acetic acid and 3.25 ml
! A mixture of concentrated hydrochloric acid was heated at reflux temperature for 3 hours.

After cooling to 0° C., the crystals were collected by filtration and washed successively with water, ethanol and diethyl ether.

After drying, 1.05 g of the title compound was obtained. yield:
89%. stand, p, >3oooC. (α) =+64.0
゜(c=0.2, DMSO).

'HNMR (CFiCOO+ppm) delta=1.
53(d, 3H).

4.46 (ABq, 28), 4.74 (m,
LH), 7.84 (tr, IH).

9.13 (s, III).

±Ennu0, 95 g of (R)-(+)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-
Pyrido(1,2,3-de)(1,4)benzoxazine-6-carboxylic acid, 5 liters of pyridine and 1.0
A mixture of g of N-methylpiperazine was stirred at reflux temperature for 8 hours.

After cooling, the reaction mixture was processed as described in Example 8.

Diethyl ether was added to the residue, and the resulting solid material was filtered and washed. The crude product was recrystallized from isopropanol to obtain 1.0 g of the title compound.

Yield: 82%. Gate, p, 224℃.

(α) = +78.3° (c = 0.2.0.05N
Na0H).

'II NMR (CDC13, ppm) delta = 1.6
3(d, 3)1).

2.39 (s, 3H), 2.58 (br, s,
411), 3.43 (M, 4H).

4.44 (ABq, 211), 4.62 (m,
LH), 7.64 (d, 1ll).

8.67 (s, IH).

1.0 g of (S)-(+)-9,to-difluoro-2,3-dihydro-2-methyl-7-oxo-7H-bi (
The procedure described in Example 10 was followed starting from S)-(+)-1,8-difluoro-2,3-dihydro-2-methyl-48-(1°4]benzoxazine.

Addition of diethyl ether gave 1.3 g of the title compound.

Yield near 8%. tq, p, 252-253°C.

[α]=-i-89.2 (c=0.2, CHCl
3).

'HNMR(CF3cOO[l, ppm) delta=1
．． 25 (tr.

3H), 1.48(d, 3)1), 4.3
0 and 4.67 (dd, 6°2H), 4.42
(Q, 28), 4.52 (m, 1tl), 7.
78 (tr.

IH), 8.93 (s, IH).

Example 22 Zin-6-carboxylic acid 1,25 g of (S)-(+)-9,1 O-difluoro-2,3-dihydro-2-methyl-7-oxo-7H
-Pyrido(1,2,3-de) (1,4) Ethyl benzoxazine-6-carboxylate was hydrolyzed and processed according to Example 11. 0.93 g of the title product was obtained. Yield: 82%. n, p.

288-289°C. [α) =+65.3@ (c=
0115, CHCj! s).

Gi! I NMR (CF3cOOD, ppm) delta =
1.43(d, 3)1).

4.26 and 4.64 (dd, d, 2H), 4.4
7 (m, IH), 7.74 (dd, IH),
8.96 (s, l1l).

0.84 g of (S)-(+)-9,10-difluoro-2,3-dihydro-2-methyl-7-oxo-7H-
and lido(1,2,3-da) (1,4)benzoxazine-6-carboxylic acid, 4. A mixture of :3nj' of pyridine and 0.85 g of N-methylpiperazine was heated at reflux temperature for 8 hours with stirring.

After cooling, the reaction mixture was processed as described in Example 12.

0.9 g of the title product was isolated.

Yield: 83%. M, 9.293-295°C.

[α]=・←46.4° (c=0.19.0.05
NNa0H).

'HNMR (Dzo, 1ON Na0D 1 drop, p
pm) Delta = 1.30 (6,3H), 2.09 (
s, 3) (), 2.35 (br, s, 48).

3.00 (hr, s, 4H), 3.64 (tr,
1tl), 4.09(m, 2H).

6.94 (d, IH), 7.97 (s, LH).

Example 24 A solution of 15.69 g diethyl azodicarboxylate in 50 mj7 tetrahydrofuran, 12.29 g 2,3-difluoro-6-nitrophenol, 11.25 g (S)-2- in 250 m1 tetrahydrofuran
Add slowly to a solution of (2-tetrahydropyranyloxy)-1-propanol and 23.68 g of triphenylphosphine. Reduce the temperature to 2 by cooling in a water bath.
The addition was completed after 1.75 hours while maintaining 5°C. The reaction mixture was stirred at room temperature overnight. The solvent was then distilled off and the residue was dissolved in diethyl ether and petroleum ether (40-6
0) in a 1:1 mixture. The solids were separated by filtration and the solution was reduced to 0. Washed 4 times with IN sodium hydroxide, once with brine and water, dried over anhydrous sodium sulfate, and concentrated to give 34.93 g of crude material. The material was chromatographed on a silica gel column (developing solution: toluene/acetone: 9/1).

Fractions containing the title product were collected and evaporated to dryness.

15.64 g of the title compound were obtained. Yield near 0%
. [α) = -13,9° (c = 1.2, CHCj!
3).

The product was found to be a 3:2 mixture of diastereomers.

'HNMR (CDCIls, I) pH) Main compound, delta = 1.33 (d, 38), 1.5-1.9 (m
, 6H), 3.49 and 3.88 (2x s,
2H), 4.1-4.4 (11+, 3H),
4.79 (tr, IH).

6.98 (m, IH), 7.65 (m, I
H).

Subcompound, delta = 1.28 (d, 38), 1.
5-1.9(-6)1), 3.49 and 3.88(
2x m, 2H), 4.1-4.4 (m.

3) 1), 4.73 (tr, IH), 6.
98(m, II(), 7.65(w.

1B).

did. A few g of oily product were obtained as a residue (yield 1
00%) was used as is in Example 26.

The product is (α) = −3,9° (c = 2.3,
CHII, ).

'HNMR (CDCj!, +, ppm) delta = 1.
26(a, 3H).

2.73 (br,!!, IH), 4.12 and 4.39 (2x m, 2H).

4.23 (m, 1B), 7.03 (m, 1
)1), 7.74 (m, IH).

3.3 g of Dowex 50W in 60-l of methanol
-X8-400H” (RTM) 3.3 g of (S)-(-)-3,4-difluoro-2-(2-(2-tetrahydropyranyloxy)propoxyconitrobenzene) in a suspension of ion exchange resin. was added while stirring.

After reacting for 40 minutes at room temperature, the ion exchange resin was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in diethyl ether, the solution was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to 10 mj! A solution of 1.15 g methanesulfonyl chloride in diethyl ether is prepared by adding 2.2 g of (S)-3,4-difluoro-2-(2- Hydroxypropoxy)nitrobenzene and 1.5 g of triethylamine were added to a stirred solution.

After 30 minutes, the reaction mixture was worked up in the usual manner (Example 2
).

3.4 g of the title product was obtained. Yield 100%.

This was used in Example 27 without further purification.

The product is [α) = −2,5° (c=2.0, CH
Cj! :+).

'HNMR (CDCfs, p9ea) delta = 1.55
(d, 3H).

3.08 (s, 3B), 4.37 (m, 21
1), 5.13 (m+18).

7.09 (steel, IH), 7.73 (m, I
B).

3.3g (S)-(-
)-3,4-difluoro-2-(2-mesyloxypropoxy)nitrobenzene was added to 0.2 g of 10% Pd.
/C and hydrogen and the reaction mixture was worked up according to Example 3.

Yield was 2.6 g of oil (100%).

The product is [α)=−3,5° (C=2, CHCj!s
) and was used in Example 28 as is.

'HNMR (CDCj!,, ppm) delta = 1.4
7(d, 3)1).

3.09 (s, 3H), 4.17 (+m, 2H
), 5.15 (m, 18).

6.43 (-, IH), 6.73 (m, IH).

2.5 g of (S) in anhydrous tetrahydrofuran of Oxazine 80a+1
)-(-)-3,4-difluoro-2-(2-mesyloxypropoxy)aniline with 2.3 g of potassium ter
T-butoxide was added for cyclization and processed as described in Example 4.

The residue was purified by column chromatography on silica gel using a developing solution of di-petroleum ether (40-60)/diethyl ether (3/2) to obtain 0.6 g of the title product. Yield 37.5%. [α)=+8.7” (c=2.0,
CHCJ3). The product was found to be optically pure as confirmed by NMR, with trace amounts of 2-allyloxy-3,4-difluoroaniline present.

'II NMR (CDC13, I) l) II) Delta =
1.20 (d, 3H).

3.51 axis, III), 3.78 and 4.
27 (2x ta, 2H).

6.26 (m, 1B), 6.56 (n+, 1l
l).

The above reaction was carried out using 3.0 g of (S)-3,4-difluoro-
The procedure was repeated using 2-(2-mesyloxypropoxy)aniline as the starting material. The residue was purified by chromatography on silica gel.Developing solution: petroleum ether (40-60)
/diethyl ether: 1/1), 0.85 g of the title product was obtained. Yield: 43%.

In addition, by-products 0,25 showing positive in the ninhydrin test
g was isolated. The structure was determined by NMR to be (3R)-7
,8-difluoro-2,3-dihydro-3-methyl-4
-((IR)-2-(6-amino-2,3-difluorophenoxy)-1-methylethyl)-(1,4)benzoxazine.

'HNMR (CDCl 3.ppm) delta = 1.2
1 and 1.35 (2x d, 211), 3.48 (
br, s, 2H), 3.6-4.3(m, 6)1)
.

6.30 and 6.47 (2x m, 21 ri, 6.
64 (m, 2H).

Tetrahydropyranyloxy)propoxy)nido!
f2 0.2 g of 60% sodium hydride, previously washed with pentane, suspended in 10 mf of tetrahydrofuran, then 3.2 g of (R)-2-(2-tetrahydropyranyloxy)-1-propanol and A mixture of 10 ml of tetrahydrofuran was added to the stirring suspension and the reaction mixture was stirred for 0.5 h.

The resulting clear solution was slowly added to a stirred solution of 0.89 g of 2.3.4-trifluoronitrobenzene in 10 ml of tetrahydrofuran while maintaining the temperature at 15-20°C.

The reaction mixture was stirred for an additional 0.5 hour and then concentrated.

Water and diethyl ether were added to the residue. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo.

The crude residue was purified by chromatography on silica gel (developing solution: hexane/diethyl ether/triethylamine: 3/210.1) to obtain 1.25 g of the title product as a mixture of diastereomers (ratio: 55/45). . Yield near 8.4%.

'II NMR (CDC1:+, pl)m) Delta=
1.30 (d, 3H) 11.33 (d, 3H),
1.4-1.9 (m, 6H), 3.50 and 3.8
8 (2x m, 211), 4.1-4.4 (m
, 3) 1), 4.75 (tr, 18).

4.79 (tr, 1N), 6.99 (m,
LH), 7.68 (m, III).

0.75 g DOWEX 50W-X8-400H”
(RTM) ion exchange resin was added to a solution of 0.75 g of (R)-3,4-difluoro-2-(2-(2-tetrahydropyranyloxy)propoxy]nitrobenzene in 15 mff of methanol under stirring. After stirring for 0.5 hours, the ion exchange resin was filtered off, and the filtrate was concentrated under reduced pressure to obtain 0.5 g of the oily title product. Yield: 95.2%.
. The product is [α) −+3.3 (c=2.4; C
HCβ,).

'II NMR (CDCl 3.ppm) delta=1.
27(d, 3)1).

2.93 (s, 1) 1), 4.12 and 4.38
(dABq, 2H).

4.23(+++, 110.7.03(m,
III), 7.73 (m, 18).

0.4 g of 60% sodium hydride, previously washed with pentane, was suspended in 201111 tetrahydrofuran. Then 2.96 g of (R)-2-(1-ethoxyethoxy)-1-propanol and 10IIl! of tetrahydrofuran was added to the suspension under stirring. 0
．． After 5 hours of reaction, the clear solution was gradually dissolved in 10 ml of tetrahydrofuran, 79 g of 2.3.4-1
-lifluoronitrobenzene and the reaction mixture was stirred for an additional 0.5 h.

The solvent was distilled off under reduced pressure, and diethyl ether and water were added to the residue. The organic layer was separated, washed with water, dried over anhydrous sodium sulphate, filtered and evaporated to dryness. The crude residue was purified by chromatography on silica gel (developing solution:
Hexane/diethyl ether/triethylaminenia/
3) 0.1).

Finally, 2.5 g of the title product were isolated as a mixture of diastereomers (ratio: 2/1). Yield: 82%.

'If NMR (CDC1z, ppm) delta = 1.
17(tr,3)1).

1.20(tr, 3)1), 1.29(m, 6
)0. 3.57 (m, 2H).

4.0-4.4(m, 3)1), 4.82(q,
1tD, 4.89 (q, 1ll).

7.01 (m, 1tl), 7.66 (m, LH
).

1.0g of DOWEX 50W-X8-400H” (R
TM) ion exchange resin was prepared by adding 2.0 g of (R)-3,4-difluoro2- (
Added to 2-(1-ethoxyethoxy)propoxyconitrobenzene solution. After stirring for 1 hour, the ion exchange resin was filtered off and the filtrate was concentrated to give 1.6 g of the title product as an oil. Yield: 100%.

The product is (α) = +4. O° (c = 2.0,
CHClz).

The NMR spectrum was comparable to that of the product obtained in Example 30.

200 mj of 5.2 g of 60% sodium hydride, which has been washed with pentane in advance! of dry tetrahydrofuran. Next, 41.6 g of (R)-2-(2-
tetrahydropyranyloxy)-1 propatool and 1
A mixture of 00 nlN of tetrahydrofuran was added to 15-2
Added to the stirring suspension at 0°C. After 0.5 hours of reaction, the clear solution was gradually injected with 100 nj! of 3-chloro-2,4-difluoronitrobenzene dissolved in tetrahydrofuran and the reaction mixture was further diluted with 0.5 g of 3-chloro-2,4-difluoronitrobenzene dissolved in
Stir for hours.

The reaction mixture was concentrated, the residue was dissolved in diethyl ether, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to give 51.0 g of crude material, (R)-3- Chloro-4-fluoro-2-(2-(2-tetrahydropyranyloxy)propoxyconitrobenzene was obtained. This product was dissolved in 300"l of methanol and 5.0g of DOWEX 50W-X8-400H" (RTM) ion exchange resin with stirring overnight. The ion exchange resin was filtered off, and the filtrate was concentrated under reduced pressure. The residue was distilled to 2
Obtained two title products: They are p, 130-1.
40℃/0.51m) 16.1g of Ig,
p, 3.3g of 140-150℃10.5IHg
So, combine both. Yield: 68.4% (corrected value).

The product is [α) = -12°5° (C = 2.0,
CHCj! s) and contained 10 mol% of 1,2-propanediol.

'HNMR (CDCI! 3.ppll) delta=1.
29(d, 3H).

2.95 (s, IH), 4.08 and 4.18 (
dABq, 2H).

4.27 (intestine, l1l), 7.10 (ml
IH), 7.87 (+*, 18).

The title product was optically pure; less than 1% of the enantiomer was detected by NMR.

Example 34 15,0 g of 3-chloro-4-fluoro-2-(2-
Hydroxypropoxy)nitrobenzene was dissolved in 200 mJ dry diethyl ether and 12.5 mJ' triethylamine. The solution was stirred and a mixture of 7.56 g of methanesulfonyl chloride and 50 ml of diethyl ether was added while maintaining the temperature at 15-20°C. After stirring for 0.5 hours, water was added and the organic layer was separated;
Washed with water, dried over anhydrous sodium sulphate, filtered and evaporated to dryness.

21.58 g of the title product was obtained. Yield: 91.2
%.

'HNMR (CDCi73.ppm) delta=1.5
4(d, 3H).

3.07 (s, 3H), 4.23 and 4.38
(dABq, 2H), 5.18(m, 1)1
), 7.13 (m, 1N), 7.87 (m,
IH).

Example 35 6.55 g of (
1.0 g of 10% palladium on activated carbon was added to R)-3-chloro-4-fluoro-2-(2-mesyloxypropoxy)nitrobenzene. The mixture was stirred vigorously at 20-25°C and saturated with H2. Required amount of H7
After the ethanol has been absorbed, a few TIf! was added to dissolve the amine. The reaction mixture was filtered through Hyflo (RTM) and the filtrate was concentrated under reduced pressure to give 6.0 g of the oily title product (100% yield). This was used as is for cyclization.

Example 36 Potassium oxide, 0.7 g powdered potassium carbonate and 85 m
g of tetrabutylammonium hydrogen sulfate overnight with stirring. Water was added to the reaction mixture and the organic layer was separated, washed with water, dried over anhydrous sodium hydrogen sulfate, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (developing solution Nidiethyl ether/
Hexane = 1/1). 0.75 g of the title product was obtained. Yield near 5%. The product is [α] = −17,9°
(c=2.0, CHC13).

'HNMR (CDCl2., ppm) delta = 1.1
7(d, 3H).

3.47 (+m, 1tl), 3.63 (s,
IH), 3.80 and 4.30 (dA8q, 2H
), 6.41 (m, 1N), 6.57 (m,
18).

Example 37 1.49 g of (R)-3-chloro-4-fluoro-2-(2-mesyloxypropoxy)nitrobenzene in 20 ml of xazine toluene was mixed with 1.12 g of powdered water in 30 ml of toluene. 3) 6.g of 2.3.4-trifluoronitrobenzene and 5.48 g of (R)-t-benzyloxy-2-propanol in 80 ml of toluene.
A stirred suspension of 72 g of powdered potassium hydroxide and 4.14 g of powdered potassium carbonate was added while maintaining the temperature between -5 and -10°C. The reaction mixture was stirred at -5°C for 30 minutes. Water was added and the organic layer was separated. The aqueous layer was washed with toluene and the combined organic layers were washed with water until neutral.

Toluene was distilled off, and the residue was purified by chromatography on silica gel (developing solution: toluene).

8.8 g of the title compound were obtained. Yield: 91%.

The product is [α) = −62,0′ (c = 2
．． 0, CHCl5').

'HNMR (CDCl x, I) pHl) delta = 1.
40(d, 3H).

3.55 and 3.65-3.73 (dd, ta, 2
8), 4.39 and 4.45 (2x d, 2t(),
4.65-4.72 (m, IH), 6.84-6
．． 92 (s.

111), 7.10-7.32 (+++, 511),
7.55-7.62 (m, 18).

isopropoxy)-3,4-difluoronitrobenzene and the mixture was stirred vigorously at 20-25°C and saturated with H.

After the required amount of H2 has been absorbed, the reaction mixture is transferred to Hyflo (
RTM) and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluting solution: diethyl ether).

4.0 g of the title compound was isolated as an oil which solidified on standing. Yield near 7%. M, p, 5B -59℃
. The product is [α) = −50,2° (c = 1.
8, CHCJ2).

'HNMR (CDC1s, ppm) delta = 1.33
(d, 3)1).

3.59-3.7Nm, 2H), 4.27(
m, III), 6.40 (n+.

IH), 6.7Nm, IH).

1.0 g of 10% Pd/C (palladium on activated carbon)
0ml of anhydrous ether and 60++7! 8 in toluene
．． 2g of (R)-2-(1-benzyloxy 20a+J
A solution of 1.94 g methanesulfonyl chloride in dry diethyl ether of 70 mj. 3.05 in dry diethyl ether
g of (R)-3,4-difluoro-2-(1-hydroxyisopropoxy)aniline and 2.53 g of triethylamine. After stirring for 3 hours at 0°C, water was added and the organic layer was separated, washed with water, dried over anhydrous sulfuric acid, filtered and evaporated to dryness.

After dissolving the residue in 70 ml of toluene, 3.36 g of powdered potassium hydroxide, 2.07 g of powdered potassium carbonate and 100 mg of tetrabutylammonium hydrogen sulfate were added and the mixture was stirred at 20° C. for 8 hours. Add water;
The organic layer was separated, washed with water, dried over anhydrous sulfuric acid, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (developing solution Nidiethyl ether/hexane: 1/1). The product fractions were combined and evaporated to dryness. The residue was dissolved in petroleum ether (40/6
0) and filtered. 0.2g solid (R)-7,
8-difluoro-2,3-dihydro-4-mesyl-2-
Methyl-C1,4)benzoxazine was obtained.

'HNMR (CDCj?3,9P thirst) delta = 1.48
(d, 3H).

2.96(s, 3)1), 3.16 and 4.24(
dd, d, 2) 1), 4.29 (m+ IH),
6,66 6.77 (n+, IH), 7.35-7
．． 43 (m, 11ri.

The filtrate was distilled off under reduced pressure to obtain 2.0 g of the title compound. Yield near 2%. This product has [α)=+38.8°(c=2.
0. CHCj! z). The optical purity was greater than 99% as shown by NMR spectroscopy. The NMR
The spectrum was similar to that of the title compound of Example 5.

11.5+wj' of ethyldiisopropylamine while maintaining the temperature at 20°C, 250+nj! was added to a stirred solution of 11.46 g of 3,4-difluoro-2-mercaptonitrobenzene in absolute ethanol. After stirring for 10 minutes, 4.94 g of (R)-1°2-propylene oxide was added, and stirring was continued for 3 hours. The reaction mixture was concentrated under reduced pressure, and water and diethyl ether were added to the residue.

The ether layer was separated and washed successively with water, 2N sodium hydroxide, and water. The organic layer was then dried over anhydrous sodium sulfate, filtered and evaporated to dryness to obtain 15.0 g of coarse material. This was purified by silica gel chromatography (developing solution Nidiethyl ether/hexane:
1/1), l 3.3 g of the oily title product were obtained. Yield: 89%. The product is [α)=-36,3°(
c = 2.0, CHCl3).

'HNMR(CDCj! 3.''I)I)11) Delta=1.257(d, 3H).

2.534 (d, IH), 2.983 and 3.17
9 (2x dd, 2B).

3.87Hn+, 1ll), 7.256(+++,
III), 7.662 (m, IH).

The reaction mixture was stirred for 0.5 hour and then allowed to cool.

This was poured into ice water and adjusted to pH=10 by adding 15% sodium hydroxide solution. The aqueous layer was extracted three times with diethyl ether and the combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (developing solution: Ni diethyl ether) to obtain 11.1 g of the title compound as an oil. This is [α) = -103,7° (c = 1.9,
CHC#:+). Yield: 97%.

'HNMR (CDCj2 z, ppm) delta = 1.2
11(d, 3)1).

2.626 and 2.889 (2x dd, 2H),
3,147 (br, s.

III), 3.703 (m, 18), 4.47
4 (br, s, 2H), 6.451 (intestine, IH
), 6.96) (III, III).

60g of stannous chloride hydrate to 100*I! of (R)-3,4-difluoro-2-(2-hydroxypropylthio)nitrobenzene in absolute ethanol. The reaction mixture was raised to boiling temperature while maintaining reflux.

A solution of 11.5 g methanesulfonyl chloride in 50 mj2 of azine in toluene was added to 10,8 mj2 in 190 m1 toluene.
g of (R)-3,4-difluoro-2-(2-hydroxypropylthio)aniline and 17.3 ml of triethylamine were added to a stirred solution while maintaining the temperature at 5°C. The reaction mixture was stirred for 0.5 hour. Next 25.0
g of powdered potassium hydroxide and 0.625 g of tetrabutylammonium hydrogen sulfate were added. After stirring for 0.5 hour, the temperature was raised to 35°C. After stirring for 3 hours,
Water was added and the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness.

The residue was purified by chromatography on silica gel (developing solution: Nidiethyl ether/hexane: 1/1). 7
．． 68 g of the title product was obtained. 74. p.:99-10
1℃. This product has [α] = +55.5° (C = 1.L
CHCl3).

Goose HN+, IR (CDCl2., ppm> tail = 1.25 (d, 3) ().

2.85 (s, 3H), 2.82-2.88 and 3.37 (m, dd, 2)1).

4.85 (m, LH), 6.96 (m, LH),
7.36 (m, LH).

Example 43 (S)-7,8-difluoro-3,4-dihydro-3-
6.9 g of methyl-2H-C1,4]benzothiazine (
S)-7,8-difluoro-2,3-dihydro-4-mesyl-3-methyl-[:1.4)benzothiazine, 8.
3g of phenol and 85+nj! A mixture of 47% hydrobromic acid was heated under reflux for 16 hours. The reaction mixture was heated to 80%
Pour onto 0g crushed ice. The solution was made alkaline by adding dilute IJ hydroxide and extracted three times with diethyl ether.

The combined ether layers were washed with water, dried over anhydrous sodium sulfate, then filtered and evaporated to dryness.

5.5 g of crude title product were obtained, which was purified by chromatography on silica gel (developing solution Nidiethyl ether/hexane: 1/1) to give 2.8 g of pure title product and 1.8 g of slightly Obtained an impure substance. The product was [α)--64,0'' (c=2.5, CHCl'3).

'HNMR (CDCj! 3. ppm) delta = 1.
29(d, 3H).

2.73 and 2.89 (2X, dd, 2H),
3.59(m, 11(), 3.82(br, s
, IH), 6.14(m, IH), 6
．． 67(m, 1)1).

Example 44 A mixture of 2.01 g (S)-7,8-difluoro-3°4-dihydro-3-methyl-2H-(i,4)benzothiazine and 2.16 g diethyl ethoxymethylene malonate was heated with nitrogen. Stir under gas and heat at 140-145°C for 3 hours. After cooling, 15 g of ethyl polyphosphate was added and the reaction mixture was heated at 140-145° C. for a further 2 hours. The mixture was then cooled, poured into ice water and extracted three times with chloroform. The combined chloroform layer
% carbonate solution and water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness.

Add diethyl ether to the residue, filter the crystalline substance,
Washed and dried to give 2.3 g of the title product. yield:
70.6%.

This compound has (Q') = -41,8° (c = 0
．． 2, CH13).

'If NMR (ChCOOD, ppm) delta = 1
．． 23 (tr, 3) 1).

1.50 (d, 3) 1), 3.10 and 3.39
(2x d, 211), 4.39(m, 2H)
, 5.14(4,18), 7.97(dd,
IO), 9.03 (s, lH).

2.0 g of (S)-9,10-difluoro-2°3-dihydro-3-methyl-7-oxo-7H-pyrido (1,
A mixture of ethyl 2,3-de)(1,4)benzothiazine-6-carboxylate, 20n+1 acetic acid and 5 ml concentrated hydrochloric acid was heated at reflux temperature for 3 hours. After cooling to 5℃,
The crystals were collected by filtration and washed successively with water, ethanol and diethyl ether.

After drying, 1.65 g of the title product was obtained. Yield: 9
1.8%. The product was [α) = -14,1° (CD = 0.25, CHCβ3). M, p, : ＞
300℃.

'HNMR (CF3cOOD, ppm) delta = 1.
52(d, 3H).

3.10 and 3.40 (2x d, 21(), 5
．． 16 (m, IH), 7.98 (dd, I
H), 9.12 (s, 1) 1).

Example 46 1,49 g of (S)-9,10-difluoro-2°3
-dihydro-3-methyl-7-oxo-7H-pyrido (
1,2,3-de) C1,4) Benzothiazine-6
- After conversion of the carboxylic acid to the corresponding chelate, it was treated with N-methylpiperazine for 24 hours as described in Example 8.

The reaction residue was mixed with 4Qmj7 methanol and 1.42ml
of triethylamine for 5 hours to reflux temperature. The mixture was cooled to room temperature and filtered to isolate 0.32 g of starting material. The filtrate was concentrated under reduced pressure to 40 cal.
of 4N hydrochloric acid was added. The residue partially dissolved and an additional 0.35 g of starting material was obtained by filtration. The filtrate was washed three times with chloroform, and the aqueous layer was adjusted to pH=11 with 4N sodium hydroxide solution, and then adjusted to pH=7.3 with IN hydrochloric acid.
Adjusted to.

The solution was extracted three times with chloroform and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was recrystallized from isopropanol to obtain 0.4 g of the title compound. Yield: 21.3%. M, p, :
260-262°C (decomposition). The product is [α) =-
It was 77.9° (c=0.2, CHCj2:+).

JI NMR (CDC1:+, ppm) delta-1,5
9(d, 3)1).

2.40 (s, 3H), 3.06 and 3.44 (
2x d, 2H), 2.733.53(br,,
8tl), 4.84 (n+, 1fl), 7.89
(d, l1l).

8.72 (s, 1ll).

11.46 g of 3,4-difluoro-2-mercaptonitrobenzene was added to 8.51 g as described in Example 40.
in the presence of N-ethyldiisopropylamine of 4.94
g of (S)-1,2-propylene oxide. Post-treatment was also similar.

13.2 g of the title product was obtained. Yield 14.4%.

The product is [α) = +35.8° (C = 2.0, C
HCl).

'HNMR (CDC13, ppm) delta = 1.26 (
d, 38).

2.64 (br,, III), 2.99 and 3.
18 (2x dd, 211).

3.87 (m, IH), 7.26 (m, 1ll)
, 7.66 (m, IH).

13.0 g of (S)-3,4-difluoro-2-(2-
Hydroxypropylthio)nitrobenzene was prepared in Example 4.
Reduction was carried out with 60 g of stannous chloride dihydrate as described in 1.

After similar work-up, 9.8 g of the oily title compound were obtained. Yield: 86%. The product is [α] = +101.8°
(c=1.2, CHCj!+).

'If NMR (CDC1x, ppm) delta-1,
21(d, 3H).

2.63 and 2.89 (2x dd, 211), 3
．． 71 (m, III), 4.18 (br,, NH
z + (ltl), 6.45 (m, 1ll),
6.96 (m, LH).

Both the mesylation and ring closure of 9.5 g of azine (S)-3,4-difluoro-2-(2-hydroxypropylthio)aniline were carried out according to the method described in Example 42. Post-treatment was also similar.

Obtained 7.0 g of solid title product. Yield: 57.6%.

phylum, p, 105-107°C. The product is [α] = −6
8.4° (c=0.9, CHCβ3).

'HNMR (CDC1s, ppm) delta = 1.25 (
d, 3)1).

2-85 (s+ 38), 2.85 and 3.36 (
2x dd, 211), 4.86 (m, IH),
4.96 (m, III), 7.36 (m,
IH).

Demesylation of 1 ml 6.9 g of (R)-7,8-difluoro-2,3-dihydro-4-mesyl-3-methyl-(1,4)benzothiazine with phenol and hydrobromic acid Example 43 I did it as described. Post-treatment was also similar.

Obtained 5.0 g of oily title product. Yield: 100%.

The product is (α) = +65.4° (c = 2.0
, ClCl1s).

The compound was found to be optically pure as evidenced by NMR.

'l(NMR(CDCl x, ppm) delta = 1.3
) (d, 3H).

2.75 and 2.91 (dABq, 211), 3.
6) (+s, IH), 3.78 (br, st I
H), 6.15 (+++, IH), 6.69
(m, IH).

A mixture of 4.7 g of ethyl carboxylate (R)-7,8-difluoro-3,4-dihydro-3-methyl-2H-(1,4)benzothiazine and 5.4 g of diethyl ethoxymethylene malonate was heated with nitrogen gas. The mixture was stirred under water and heated at 140-150°C for 8 hours. After cooling, 37.5 g of ethyl boronate was added and the reaction mixture was heated at 140-145<0>C for 4 hours. Work-up was similar to that described in Example 44. In this way, [α'! =+44.8°
5.1 g of the title product (c=0.2, CHC13) was obtained. Yield: 6? , 1%.

'HNMR (CF, C00D, ppm) delta = 1.
29 (tr, 3H).

1.55 (d, 3) 1), 3°15 and 3.45
(dABq, 2B), 4.47 (m, 2H),
5.20 (m, LH), 8.06 (tr, L
H), 9.09 (S, IH).

Example 52 5.0 g of (R)-9,10-difluoro-2゜3-dihydro-3-methyl-7-oxo-7H-pyrido (1,
Ethyl 2,3-de)(1,4)benzothiazine-6-carboxylate was treated as described in Example 45 with 50 nl acetic acid and 12.5 mff1 concentrated hydrochloric acid. Work-up was carried out in the same manner to obtain 3.95 g of solid title product. Yield: 86.4%. M, 9°278°C (decomposed).

The product is (α) = +14.6° (c = 0.27,
CHCl1).

'HNMR (CFsCQOD, ppm) delta = 1.
54(d, 3B).

3.11 and 3.42 (dABq, 2H), 5.1
7 (m, III), 8.00 (tr, IH),
9.14 (s, 18).

3.78 g of (R)-9,10-difluoro-2°3-
Dihydro-3-methyl-7-oxo-7H-pyrido (1
,2,3-de)(1,4)benzothiazine-6-carboxylic acid was converted to the corresponding chelate and then treated with N-methylpiperazine for 48 hours as described in Examples 8 and 46. The reaction residue was dissolved in 10,100 l of 95% methanol and 6.5+sf of triethylamine and refluxed for 3 hours. Cool the mixture to room temperature and add 100 ml of 4
N hydrochloric acid and 100o+j! of chloroform was added. Undissolved substances were filtered and recrystallized from ethanol.1.
Obtained 2 g of the title product. M, p, 257-259°C.

The product is [α) = +83.7° (c = 0.2, C
It was H (J!,).

Separate the aqueous layer from the filtrate, wash twice with chloroform,
After adjusting pn=ti with 4N sodium hydroxide solution,
The pl was adjusted to +7.3 with IN hydrochloric acid. Aqueous fraction 100
Extracted with three ml portions of chloroform, the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was recrystallized from ethanol to obtain 1.6 g of the title compound. This compound has [α) = +83.
3° (c = 0.2, CHClz). M,
I), 262-265°C.

Both fractions of the title compound were nearly pure as confirmed by NMR. Shrinkage rate: SS, O%.

'HNMR (CDCj!s, a few drops of DMSO (mouth 6
), ppm) delta = 1.58 (d, 3H),
2.42 (s, 3) 1), 2.42.2.88° 3.09 and 3.44 (4x br, s, 8) 1),
3.07 and 3.44 (dABq, 2B),
4-91 (a++ 1ll), 7.88 (d, I
H).

8.79 (s, III).

12.0 g of 2-chloro-3-fluoro-6-nitrothiophenol to 250 mj! was dissolved in absolute ethanol. After adding 11.2 liters of ethyldiisopropylamine, the solution was stirred and the temperature was maintained at 20<0>C, followed by the addition of 3.82 g of (S)-propylene oxide. The crystalline thioferulate formed immediately after the addition of the base dissolved within a few hours. The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was dissolved in diethyl ether and washed with water, 0.1N sodium hydroxide solution, again with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. , 14.71g
A set of substances was obtained. The product was purified by chromatography on silica gel (developing solution: petroleum ether (40-6
0)/diethyl ether: 1/1).

Obtained 13.71 g of the title product. Yield: 89%. The compound is [α) = +67.8° (c = 7.7, CHC
j! :+).

'II NMR (CDC1x, Ppln) delta=1.
24(d, 3H).

2.93 and 3.14 (2x dd, 211), 3
．． 86 (m, 1tl), 7.29 (dd, IH
), 7.59 (dd, l11).

28.2 g of stannous chloride was dissolved in 6.94 g of (S)-3-chloro-4-fluoro- in 50 mf absolute ethanol.
Added to a stirred solution of 2-(2-hydroxypropylthio)nitrobenzene. Shortly thereafter the temperature rose to 50°C. The reaction mixture was stirred for 0.5 h and then for an additional 1.5 h.
g of stannous chloride was added and the mixture was heated under reflux for 1 hour. The reaction mixture was cooled, poured onto 250 g of crushed ice, and adjusted to pH=10 by adding 2N potassium hydroxide solution. The aqueous layer was extracted three times with diethyl ether. The combined ether layers were washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to yield 5.76 g of the title product. Obtained. Yield: 93%, the product was [α) = -53,6° (CD; 1.0, CHCj!s).

'HNMR (CDCl s, pp@) delta = 1.21
(d, 3H).

2.63 and 2.96 (2x dd, 28), 3
．． 20 (br, s, IH).

3.68 (s+, 18), 4.5Hbr, s, 2
H), 6.62 (dd, 1) 1).

6.96 (dd, IH).

4.7 g of (S)-3-chloro- in 75 liters of toluene
A solution of 4-fluoro-2-(2-hydroxypropylthio)nitrobenzene and 6.9+Il of triethylamine was stirred and cooled to 5<0>C. Add a solution of 4.6g methanesulfonyl chloride in 20all toluene,
The mixture was stirred for 0.5 hour.

Addition of mesylating agent did not affect the product composition. Next, 10 g of powdered potassium hydroxide and 0.25
g of tetrabutylammonium hydrogen sulfate was added and the reaction mixture was stirred overnight. 100nj! of toluene and 5
0 ml of water was added and the organic layer was separated, washed with water and evaporated to dryness to give 6.32 g of crude material. This was purified by silica gel chromatography (developing solution: petroleum ether (40-60)/diethyl ether: 1/
I). 5.12 g of the title product was isolated. Yield: 86
%. The product is (α) = -53,6° (c = 1.0
, CHCl,).

'HNMR (CDCj! s, l) pm) delta = 1.
23(d, 3B).

2.84(s, 3)1), 2.90 and 3.43
(2x dd, 2H).

4.84 (s, l1l), 6.96 (dd, IH
), 7.49 (dd, IH).

Example 111 Gomiazine 4.47 g of (R)-8-chloro-7-fluoro-2,
3-dihydro-4-mesyl-3-methyl-(1,4)benzothiazine and 5.0 g of phenol were added to 501111
of 48% hydrobromic acid. The mixture was refluxed for 17
The reaction mixture was heated for 0 minutes and then cooled and poured onto 500 g of crushed ice.

A solution of 20 g of sodium hydroxide in 100 m# of water was added and the aqueous layer was extracted three times with diethyl ether.

The combined organic layers were washed with 2N sodium hydroxide solution,
Saturation with sodium chloride solution, drying over anhydrous sodium sulfate, filtration and evaporation to dryness gave 3.67 g of crude material. This was purified by chromatography on silica gel (developing solution: petroleum ether (40-60)/diethyl ether: l/1). 3.13 g of the title product was obtained, which was [α) = +6). 2° (c=2.1
It was CH(Jz). Yield: 95%.

NMR analysis revealed that the optical purity was greater than 99%.

Electron HNMR (CDCj2 *, ppm) Delta = 1
．． 28 (d, 3) 0°2678 and 2.93 (2x
dd, 211), 3.56 (+n, IH), 3
．． 79 (br, s, III), 6.29 (
dd, 11 amount) + 6.68(dd, IH
).

4,35 g of (R)-8-chloro-7-fluoro-3
,4-dihydro-3-methyl-2H-(1°4)benzothiazine and 4.42 rs of diethyl ethoxymethylene malonate were stirred under nitrogen gas to give 140-
Heated at 145°C for 7 hours.

After the mixture was allowed to cool overnight, 32 g of ethyl polyphosphate was added and the reaction mixture was heated at 140-145° C. for 6 hours.

Post-processing was similar to that described in Example 44, resulting in 5
．． 98 g of the title compound were obtained. Yield: 88%, the compound has (α) = +53.0'' (c = 0.17, C
It was H (1'3).

'HNMR (CDC13+acetone (D6), ppm
) Delta = 1.29 (tr, 38), 1.56 (
d, 3H), 3.24 and 3.55 (dABq,
211), 4.47 (m, 2H), 5
．． 25 (m, IH).

7.99 (d, IH), 9.17 (s, L
H).

'HNMR (CF+COO+ppm) delta=1.
49(d, 3+1).

3.13 and 3.46 (2x dd, 211), 5
．． 15 (m, IH), 7.89 (d, III)
, 9. IHs, IH).

5,86 g of (R)-10-chloro-9-fluoro-
Ethyl 2,3-dihydro-3-methyl-7-oxo-7H-pyrido(1,2,3-del (1,4)benzothiazine-6-carboxylate) was prepared as described in Example 45 at 55++4! It was treated with acetic acid and 15 ml of concentrated hydrochloric acid. Work-up was carried out in the same way to obtain 4.62 g of the title compound, which was [α] == + 25.3° (c =
0.2, CHClz).

1,50 g of (R)-10-chloro-9-fluoro-
2,3-dihydro-3-methyl-7-oxo-7H-pyrido(1,2,3-de) (1,4)benzothiazine-6-carboxylic acid was dissolved in 1501111 acetic acid,
It was heated to 100°C while stirring.

Then 6) 111 30% hydrogen peroxide in 30 mf acetic acid was slowly added. Temperature rose to 110°C and stirring increased to 3
It lasted for hours. The reaction mass was cooled to 15° C., the precipitated solid was collected by filtration, washed with diethyl ether and dried to give 0.3
) g of by-product was obtained. IR analysis suggested oxidation of saffron (KBr: 133). 1142cm-')
, Yield: 19%.

The filtrate was concentrated under reduced pressure. The residue was treated with diethyl ether, collected by filtration, washed with water, ethanol and diethyl ether, and dried under vacuum to give 1.08 g of the title product.

Yield: 69% (uncorrected value).

Although NMR analysis has provided much evidence for the structure of the title product, its purity leaves much to be desired.

'II NMR (CF3GOOD, acetone (D6),
ppm) delta=1.7(m, 3fl), 3.
2 and 3.5 (2x m, 2H), 5. OCtm
, 11), 8. Hd, IH), 9.0(s
, 18).

The mixture was poured into 35 ml of dimethyl sulfoxide with stirring, and 2.0 g of N-methylpiperazine was added. The reaction mass was heated at 140° C. for 1 hour.

Thereafter, the reaction mixture was cooled and the solvent was distilled off.

The residue was mixed with methanol, filtered, and the filtrate was concentrated under reduced pressure to obtain 2.15 g of crude material. The mass did not crystallize from ethanol and the solution was concentrated under reduced pressure.

The residue was then stirred with 25 ml of ethanol and filtered.
0.3 g of solid material was obtained. This is silica gel TLC
Analysis (Developing solution: n-butyl alcohol/acetic acid/water: 2
It consisted of two products, as shown by /1/1).

The mixture was used as is in Example 62.

-Oxide 0.85g crude (R)-10-chloro-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-
Pyrido (1,2,3-de) (1,4)benzothiazine-6-carboxylic acid 1-oxai 0.3 g of the crude material prepared as described in Example 6) was dissolved in 30 ml of dry dimethylformamide. ,Q,35mj! of phosphorus tribromide was added at O-5°C. The reaction mixture was stirred at low temperature for 0.5 hour. Water was added to the reaction mass and evaporated to dryness. Toluene was added to the residue and evaporated. After repeating the process once, the residue is 20mj! dissolved in water. The aqueous layer was extracted with chloroform, adjusted to pl=7 with 2N sodium hydroxide solution, and extracted twice with chloroform.

The combined organic layers were concentrated under reduced pressure to obtain 0.15 g of solid product. This is a TLC analysis of silica gel (developing solution: n
-butyl alcohol/acetic acid/water: 2/1/l) was found to have R1 values comparable to the product prepared in Example 53. M, p, 255-257°C. The compound has [α) = +78.7° (C = 0.5, CH
Cfi).

'HNMR (CDCβ3)1'p) delta = 1.60
(d, 3+1).

2.40 (s, 38), 2,40.2.87.3
．． 06 and 3.43 (4xbr, s, 811), 3
．． 06 and 3.46 (2x dd, 28), 4.8
7 (m, IH), 7.87 (d, IH),
8.74 (s, LH).

17 g of (R)-2-mercapto-1-propanol and 7.49 g of 2.3.4-1-lifluoronitrobenzene were dissolved in 75 ml of dry toluene and -10
Add slowly to a stirred suspension of 4,39 g powdered potassium hydroxide in 75 IIll toluene cooled to 75°C. The mixture was stirred at this low temperature for 1 hour.

TLC analysis (silica gel, diethyl ether/hexane: l/1) showed that half of the starting material had been converted to the two products. After the reaction mixture was left at room temperature over the weekend, water was added and the toluene layer was separated, washed with water and evaporated under reduced pressure to obtain 7.65 g of agglomerates. This was purified by silica gel chromatography using 2.37 g of developing solution Nidiethyl ether/hexane: 1/1).
The title product was obtained, but it was not pure. yield:
21% (uncorrected value).

Furthermore, 3.80 g of (R)-1-(2,3-difluoro-6-nitrophenoxy')-2-(2゜3-
Difluoro-6-nitrophenylthio)furopane was isolated. Yield: 44.3%, 2. 3. Based on 4-trifluoronitrobenzene.

'HNMR (CDCjl+, ppm) delta = 1.
34(6,38).

3.6)(m, IH), 7.28(m, I
H), 7.62 (m, IH).

Example 64 75mj! 4.88 g of (S)-2-mercap)-1-propanol was dissolved in 3 toluene with stirring.
．． 51 g of powdered potassium hydroxide were suspended.

The reaction mixture was cooled to -15°C and heated to 75mj! 8.85 g of 2.3.4-)lifluoronitrobenzene dissolved in 8.5 g of toluene was slowly added. The reaction mixture was heated to -15°C.
The mixture was stirred for 2 hours. Thereafter, the cooling bath was removed, and the reaction mixture was extracted twice with water. The organic layer was dried over anhydrous sulfuric acid, filtered and evaporated to dryness to give 11.55 g of crude residue. This was purified by silica gel chromatography (developing solution: petroleum ether (40-60)
/diethyl ether: 1/1). 5.06 g of raw material was recovered. Yield: 57%.

Additionally, 3.43 g of the title product were obtained. Yield: 6
4.5% (corrected value). The product is [α] = + 39.2
° (c=1.0, CHC' f ,).

'HNMR (CDC1s, ppm) delta = 1.3
3(d, 3H).

3.63 (m, IH), 7.28 (m, IH)
, 7.6) (m, IH).

15 g of stannous chloride dihydrate were dissolved in 3.0 g of (S)-3,4-difluoro-2-(
1-Hydroxyisopropylthio)nitrobenzene was added to the stir bar solution. The reaction mixture was stirred for 1 hour, during which time its temperature rose to 62°C. Post-processing is Example 55
It was similar to that described in .

1.93 g of oily title product was obtained, which was [α]
=+11.2° (c=0.86, CHC1,).

'II NMR (CDC13, pp+w) delta=1.
65(d, 3H).

3.2 (m, IH), 3.5 (m, 28), 6
．． 48 (a+, E), 6.99 (m, 18).

Both mesylation and ring closure of 1.8 g of azine (S)-3,4-difluoro-2-(1-hydroxyisopropylthio)aniline were performed according to the method described in Example 42. Post-treatment was also similar.

1.5 g of solid title compound was obtained. Yield 65.1%
, the compound has [α) = -114,3° (c=1.
01, CHCl5).

'HNMR (CDCl x, ppm) delta = 1.42
(d, 3H).

2.90 (s, 3H), 3.00 and 4.48 (
2x dd, 2tl).

3.40 (a+, 1ll), 6.9Hm, IH
), 7.37 (+o, 18).

Example 67 1.5 g of (S)-7,8-difluoro-2,3-sihydro-4-mesyl-2-methyl-(1,4)benzothiazine, 1.8 g of phenol and 18.5 ff+1 of 4
A mixture of 8% hydrobromic acid was heated under reflux for 8 hours. The reaction mixture was cooled and poured into 150 mf of water. The solution was made alkaline with dilute sodium hydroxide solution and extracted three times with diethyl ether.

The combined ether layers were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 1.4 g of the title compound. This was [α]=−55.2° (c=1.9, CHCji! 3). Yield: 9
3%.

'HNMR (CDCj!s, ppm) delta = 1.
38 (6th, 3rd).

3.18 and 3.55 (2x dd, 2H),
3.32 (m, LH), 6.18 (m, 1
) I), 6.69 (m, IH).

Example 68 7.0 g (R)-2,3-isopropylidenedioxy-1-propanol and 8.85 g of (R)-2,3-isopropylidenedioxy-1-propanol in 75 ml of toluene
A solution of 2.3.4-g of trifluoronitrobenzene was slowly added to a stirred suspension of 4.3 g of powdered potassium hydroxide in 75 ml of toluene, maintaining the temperature at -10<0>C. The reaction mixture was then stirred at this low temperature for 0.5 h. Add water to the reaction mixture, extract and separate the organic layer,
Washed with water, dried over anhydrous sodium sulphate, filtered and evaporated to dryness. Oily residue containing 10 mol% toluene16. Obtained Og. Yield: 100%.

'HNMR (CDC1'a, ppm) delta = 1.37
(s, 3H).

1.42(s, 3)1), 3.96 and 4.16
(2X dd, 28).

4.23 and 4.34 (2X dd, 2H),
4.50 (m, IH).

7.02 (m, LH), 7.68 (m, IH)
.

After carefully drying the compound under reduced pressure, [α) =
+8.54° (c=2.6, CHC63).

Real j trowel m 3.5g DOWEX 50W-X8-400H” (R
TM) ion exchange resin in 150 nl methanol.
．． 0 g of (R)-3,4-difluoro-2-(2,3
-isopropylidenedioxypropoxy)nitrobenzene (purity 90%). The mixture was stirred overnight and then filtered to remove the ion exchange resin.

The filtrate was concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (developing solution: diethyl ether),
Oily title compound 1 containing traces of diethyl ether
0.2 g was obtained. Yield: 88%. The product is [α)=−
15,0° (c = 0.7, CH(J,) 'II NMR (CDC13) ppm) delta = 3.0
0(br,s.

IH), 3.57 (br, s, III), 3.
73 and 3.83 (2x dd.

2H), 4.13 (m, 18), 4.34 and 4
．． 43 (2x ts, 2H).

7.02 (m, IH), 7.71 (m, 18)
.

JLL71 10.0 g of (R)-3,4-difluoro-2-(2
,3-isopropylidenedioxypropoxy)nitrobenzene in 80I111 of absolute ethanol and 1.0 g
of triethylamine.

Next, 1.0 g of 10% Pd/C was added, and the mixture was
The mixture was vigorously stirred at -25°C and saturated at 1□.

After the required amount of H2 has been absorbed, the mixture is heated to Hyflo (R
TM), and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether, the ether layer was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness.
Oily title compound contaminated with 5 mol% toluene 6.65
I got g.

'HNMR (CD (1!3.ppm) delta = 1.40
and 1.47 (2x s, 6) 1), 3.8-4
．． 0m, 411), 3.73(br, s.

211), 4.43(+n, If blatant)+
6.36 (m, 1ll), 6.70 (m.

IH).

The synthesis was repeated according to the method described above. The title compound thus obtained was (α) = +11.9° (c =
2.4, CHCl,).

Luaniline 2.43 g of (R) in 10 ml of pyridine -3°4
-Difluoro-2-(2,3-isopropylidenedioxypropoxy)aniline to a stirred solution of 10 mj! A solution of 1.9 g of p-toluenesulfonyl chloride in pyridine was mixed dropwise. After stirring the reaction mixture overnight, it was evaporated under reduced pressure and the residue was dissolved in toluene. The solution was distilled off again to completely remove the pyridine. The residue was dissolved in diethyl ether. The ether solution was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to yield 4.0 g of crude material. This was purified by chromatography on silica gel (developing solution: Nidiethyl ether/hexane: 3/2). 3.6 g of the title compound were obtained. Yield: 88%. This is [α) = +8
．． 3° (c = 0.8, CHCl: +) - Self-HNMR (CDC123, ppm) Del = 1.48
and 1.56C2x s, 6) 0. 2.37 (8,
3) 1), 3.7-4.1 (m, 411).

4.34 (m, IH), 6.85 (m, IH)
, 7.21 and 7.67 (ABq, 4.10.
7. '34(m, II(), 8.07(s, I
H).

2.7 g
The title compound was obtained as an oil. Yield: 96%.

This is [α) = +142.8° (c = 0.8
, CH(/!3).

'HNMR (CDC13,139m) delta=2.33
(s, 3)1).

3.7-4.0 (+++, 4H), 4.05 (m
, Hl), 6.77(ll+l1l).

7.21 (m, IH), 7.20 and 7.68 (
^Bq, 4H).

0.6g DOWEX 50W-X8-400H” (R
TM) The ion exchange resin was dissolved in 30 ml of methanol.
1 g of (R)-3,4-difluoro-2-(2,3-isopropylidenedioxypropoxy)-N-)silaniline was added to a stirred solution.

The suspension was stirred for 18 hours. TLC analysis on silica gel (developing solution Nidiethyl ether) showed that some starting material remained, but adding 0.6 g of fresh Dowex resin had no effect. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel. A solution of 0.87 g diethyl azodicarboxylate in 10 Ill of tetrahydrofuran was chromatographed with 1.6 g of (S)-3°4-difluoro-2-(2,3) in 25 ml of dry tetrahydrofuran. -dihydroxypropoxy)-N-)silaniline and 1.3) g
was added dropwise to a stirred solution of triphenylphosphine at room temperature. After stirring for 2 hours, TLC analysis on silica gel (
The developer (nidiethyl ether) indicated complete conversion of the starting material.

The reaction mixture was concentrated, diethyl ether was added to the residue, and solid triphenylphosphine oxide was collected by filtration. The filtrate was distilled off under reduced pressure, and the residue was purified by chromatography on silica gel.
Hexane: 9/1), yielding 1.4 g of the title product. It was found to be optically pure (>99%) @
The core compound was contaminated with 16 mol% diethyl ether and 14 mol% diethyl azodicarboxylate.

'HNMR(CDCj!*, I)pm'') delta=2.
40(s, 3)ri.

2.66 (br, s, IH), 3.15 and 4.2
8 (dd, d, 2+1).

3.4-3.7 (m, 2+1), 4.42 (m,
III), 6.78 (m, 1ll).

7.26 and 7.38 (^Bq+ 48), 7.6
6 (m, IH).

1.8 g of (R)-7,8-difluoro-2,3-dihydro-3-hydroxymethyl-4-tosyl-(1,4)
Benzoxazine was dissolved in 10 mff1 of dichloromethane, the solution had been cooled to -70°C, 1a+/ of diethylaminosulfuric acid trifluoride and 10n+j! of dichloromethane was slowly added to the stirred mixture. The mixture was stirred at the low temperature for 2 hours and at room temperature overnight. Ethanol was added and stirred for 10 minutes to decompose excess trifluorodiethylaminosulfate. Add water, separate the organic layer,
It was washed with water and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (developing solution: hexane/diethyl ether: 1/1) to give 0.6 g of the title product, which solidified on standing. It contained slightly impurities.

The title product had been prepared previously in the same solvent as above, but initially at room temperature and finally at 40°C.

Only 0.2 g of impure title product was obtained from 2.0 g of starting material. The structure was confirmed by NMR.

Kan II NMR (CDCll 3.ppn+) delri=
2.34 (s, 3H).

3.23 (m, 1ll), 4.3-4.6 (m,
3) ri, 4.63 (m, l1l).

6.81 (m, IH), 7.30 7.50 (A
Bq, 411), 7.68 (m, LH).

(c=1.1, CHC13).

'It NMR (CDCl :lIppm) delta=3
．． 76 (m, LH).

4.03 (br, s, 1ll), 4.21 (m
, 211), 4.46 (m, 21+).

6.3) (m, IH), 6.59 (m, 1
ll).

1.1 g of (R)-7,8-difluoro-3-fluoromethyl-2,3-dihydro-4-tosyl-(1,4)
Benzoxazine, 1.4g phenol and 15ml
of 48% hydrobromic acid was heated at 100° C. for 3 hours. TLC analysis on silica gel (hexane/diethyl ether:
1/1) indicated the formation of more than one product and the disappearance of starting material. Pour the reaction mass onto ice and add 4 ml to the solution.
It was made alkaline by adding N sodium hydroxide solution. The aqueous layer was extracted three times with diethyl ether. The combined ether layers were dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel using the developing solution Nidiethyl ether/hexane:
1/1) 5.0.15 g of the oily title compound was obtained.

This is [α) = +29.4°, 3.5 g of 2,3-difluoro-6-nitrophenol, 3.88 g of ethyldiisopropylamine, and 6.
56 g of (R)-benzyl glycidyl ether to 30
Dissolve mj+ in ethanol and add Carius
) The mixture was transferred to a tube and heated at 120°C for 4 hours.

The reaction mixture was cooled and evaporated under reduced pressure. The residue was partitioned between water and diethyl ether. Separate the ether layer and add water,
Washed with dilute sodium hydroxide solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue, 9.82 g of a dark oil, was purified by chromatography on silica gel, developing solution: hexane/diethyl ether: 1/1), and the title compound and its regioisomer, 3-benzyloxy-1-hydroxy. 4.07 g of a 4=1 mixture of isopropoxy derivatives were obtained. Yield: 60%, the mixture was used as is in Example 77.

'HNMR (CDCl x, ppm) delta = 3.64
(d, 21+).

4.18 (m, l1l), 4.33-4.43 (
m, 2tl), 4.56 (s.

2H), 6.96(m, IH), 7.32(
m, 511), 7.67 (m.

111).

3.73 g of the mixture prepared in Example 76 was stirred,
Dissolved in 25 mA absolute ethanol.

Upon addition of 12.41 g of stannous chloride dihydrate, the reaction temperature rose to 50°C. After stirring for 0.5 hours,
The transformation was not complete. An additional 2.5 g of stannous chloride dihydrate was added and the mixture was stirred at 40° C. for 1 hour. The reaction mass was poured onto 100 g of crushed ice. The precipitate was dissolved by adding 2N sodium hydroxide solution, and the aqueous layer was extracted three times with diethyl ether. The combined ether layers were washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to yield 3.3 g of the combined material. This was purified by chromatography on silica gel (developing solution: diethyl ether), 1.37
g of the title product, 0.28 g of its regioisomer (
A mixed fraction of 3-benzoyl-1-hydroxyisopropoxy derivative) and 0.87 g was obtained, indicating that sufficient separation was not achieved. Shrinkage rate:
2.57g, 72%.

'HNMR (CDC13, ppm) delta = 3.58 (
m, 2H).

4.10-4.11 (m, 2H), 4.06 (m
, IH), 4.52 (s.

2H), 6.30 (ITl, IH), 6.6
8 (m, IH), 7.29 ([11°5 days).

Regioisomer, delta = 3.8 (m, 4H),
4.20 (m, IH), 4.56 (s, 2H)
, 6.34 (m, IH), 6.70 (m,
E), 7.3) (m, 5H).

0.84 g of the mixed fraction prepared in Example 77 was dissolved in 15 mf of dry pyridine while stirring. 10ffil
1.08 g of p-toluenesulfonyl chloride in dry pyridine was added slowly at room temperature. The reaction mixture was heated to 24
After stirring for an hour, 0.28 g of p-toluenesulfonyl chloride and 0.07 g of N-methylimidazole were added and stirring continued for an additional 26 hours. Finally, 0.3
6 g of p-toluenesulfonyl chloride was added.

After stirring the reaction mixture for 22 hours, pyridine was distilled off. The residual liquid was distilled off azeotropically using toluene and heptane. The residue was mixed with water and extracted twice with diethyl ether. The ether layer was washed twice with dilute hydrochloric acid, once with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue (1
, 8g) was purified by chromatography on silica gel to obtain the title product, developer: petroleum ether (40-60)/diethyl ether: 0.90. Yield: 63%.

In a previous experiment, 1 in dry pyridine of 15I111
．． 1.4 g of (R)-2-(3-benzyloxy-2-hydroxypropoxy)-3.4-difluoroaniline was dissolved in 10 mA of dry pyridine. 4
7 g of p-)luenesulfonyl chloride. The reaction mixture was stirred at room temperature for 1 hour. Work-up, including chromatographic purification, was performed as described above. 0. 23 g of the title compound were obtained.

'H NMR (CDC 12 z, ppm) delta = 2.32 (S, 3) 1).

2, 44 (s, 3) 1), 3.55 (d. 2H
), 3.9-4.1 (m.2H).

4, 51 (q. 2H), 4.88 (m. IH)
, 6.80m. IH).

7, 1-7.8 (m. 14H).

Additionally, 0.90 g of (R)-2-(3-benzyloxy-2-hydroxypropoxy)-3,4-difluoro-N-tosylaniline was isolated.

'II NMR (CDC j' s, ppm) delta = 2.33 (s, 3fl).

3, 5 (Kaku. 3B), 3.83-3.98
(m, 211), 4.05 (m.

IH), 4.58 (s. 2H), 6.83 (
m. 1B), 7.14 and? ．． 66 (＾Bq.
4H), 7.3 (m, 6H).

0.80 g of (R)-2-(3-benzyloxy-2-hydroxypropoxy)-3,4-difluoro-N-tosylaniline was tosylated according to the first method described above. As confirmed by NMR, 0. 7
8 g of the title compound was obtained, but contained unknown by-products. Furthermore, 0. 15 g of unreacted raw material was recovered.

1,45 g of slightly impure (R)-2- (3
-benzyloxy-2-tosyloxypropoxy)-3
．． 4-Difluoro-N-)silaniline was dissolved in 40 ml of dry toluene with stirring.

0.0 to the solution. 3 2 g powdered potassium carbonate, 0.6
g of powdered potassium hydroxide and 0.g of powdered potassium hydroxide. 0.4 g of tetrabutylammonium hydrogen sulfate were added sequentially. The suspension was stirred at room temperature for 2.5 hours. After that, water was added, and the organic layer was separated, washed with water, and evaporated to dryness to obtain 1.33 g of composite material. This was purified by chromatography on silica gel, developing solution: petroleum ether (40-60)/diethyl ether: 1/1), 0.51 g of pure title product and 0.51 g of pure title product. 64 g of a mixture was obtained. The latter was crystallized from hexane/tetrahydrofuran and 0. 3 3
The title compound of g was obtained. Total acid rate: 0.84g (80%
).

'H NMR (CDCl s.pps+) delta = 2.38 (s, 3B).

3, 12 and 4.33 (2x dd, 2H), 3.3
5-3.55 (+n, 2+1).

4, 50 (m. 3H), 6.74C++, IH
), 7.26 (m. 5H).

7, 29-7.46 (^Bq, 4) 1), 7.6
) (m. LH).

0,6) g of (S)-3-benzyloxymethyl-7
, 8-difluoro-2,3-dihydro-4-tosyl-(
1,4) Benzoxazine was dissolved in 50ml absolute ethanol and 20mf toluene. 10% of 0.1g
After adding Pd/C and stirring the suspension vigorously, H2
saturated with. After the required amount of H8 has been absorbed, the catalyst is filtered off with Hyflo (RTM) and the filtrate is distilled off under reduced pressure to give 0.
52 g of product was obtained. This was found to be a 1:1 mixture of raw material and reduction product by TLC analysis.

The reduction step was repeated and no further conversion to reduced product was observed. Thereafter, the residue was purified by chromatography on silica gel and the developing solution was Nidiethyl ether/Petroleum ether (40-60): 5/1).
0.29 g of starting material was obtained as evidenced by NMR. Furthermore, 0.23 g of the title compound was obtained. Yield: 9B, 1% (corrected value).

The compound has [α) = −130,5° (c = 1
．． 0, CHCl,).

'HNMR (CDCj! 3.PpIll) delta = 2
．． 40 (s, 3H).

3.15 and 4.26 (2x dd, 211), 3.
51-3.66 (m, 211).

4.42 (m, IH), 6.78 (m, IH)
, 7.27-7.48 (ABq.

4H), 7.67 (m, IIri.

The compound was identified as a 95:5 mixture of the title product and its optical isomers.

7.0 g of (S)-1-(4
, 4'-dimethoxytrityloxy)-2-propanol and 3.54 g of 2.3.4-trifluoronitrobenzene was cooled to -10°C in a 30mj! was added slowly to a stirred suspension of 2.8 g of powdered potassium hydroxide in toluene. Remove the cooling bath and let the mixture stand at room temperature for 1 hour.
Stir for hours. TLC on silica gel showed that no reaction had occurred. Next, 0.1 g of tetrabutylammonium hydrogen sulfate was added and the mixture was stirred for 19 hours. Add water, separate the organic layer and wash with water,
It was concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (eluant Nidiethyl ether/hexane: 2/3) to yield 5.7 g of pure viscous title compound and an additional 1.0 g slightly impure amount. .

'HNMR (CDCIl, ppm) delta = 1.3
2(d, 3H).

3.27 and 3.39 (dABq, 2H), 3
．． 78 (s, 6H), 4.6) (m, IH)
, 6.7-7.3(m, 13H), 6.92(
m, 1)1).

7.66 (m, IH).

Example 82 5.5 g of (S)-2-(1-(4,4'-dimethoxytrityloxy)isopropoxy]-3.4-difluoronitrobenzene was dissolved in 100 ml of methanol with stirring. 3 .5g DOWEX 50W-X8
-400H" (RTM) ion exchange resin was added and the suspension was stirred for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure.

The residue was purified by chromatography on silica gel (developing solution Nidiethyl ether/hexane: l/1), 2.
Obtained 0 g of the title compound. This is = -71,4° (c
=1.4, CHCj! Yield: 86%.

(COC1s, I’pm) 2H), 4.71 (m.

IH).

[α]

there were.

'HNλIR 2,79 (m.

7, 67 (m.

Example 83 Delta = 1.40 (d, 3H).

IH), '6.99 (m, IH).

A solution of 1.15 g of methanesulfonyl chloride in 10 ml of dry diethyl ether was dissolved in 2.1 g of methanesulfonyl chloride in 50 ml of dry diethyl ether, maintaining the temperature at 15-20°C.
1 g of (S)-3,4-difluoro-2-(1-hydroxyisopropoxy)nitrobenzene and 1.5 g of triethylamine were added slowly to the stirred mixture. The mixture was stirred for an additional 0.5 hour and water was added. The organic layer was separated, washed with water, dried over anhydrous sulfuric acid, filtered and concentrated in vacuo to give 2.8 g of the title compound as an oil. This is [α] = ÷ 57.1' (C = 1
．． 3, CHCJ,). Yield: 100%.

'II NMR (CDC1t, ppm) delta=1.
46(d, 3)1).

3.03(s, 38), 4;38(m, 2H)
, 4.82 (m, 1B).

7.05 (n+, LH), 7.70m, l
1l).

2.6 g of (S) dissolved in 70 mA absolute ethanol
)-3,4-difluoro-2-(1-mesyloxyisopropoxy)nitrobenzene, 0.3 g of 10% Pd
/C was added. After stirring the mixture vigorously, 20-
Saturated at 25°C and Hz. After the required amount of H2 was absorbed, the reaction mixture was treated according to Example 3. 1.8g
The title compound was obtained as an oil. This is (α) = +13.7°
(c=0.65, CHCj!3). Yield near 6.6%.

'HNMR (CDC1', ppm) delta
=1.39(d, 3B).

3.06 (s, 3H), 4.36 (dABq,
2H), 4.56 (m, 1ll).

6.39(m, 1)1), 6.73(a+, l
1l).

Yu111Li lQn/! of (S)-3 dissolved in toluene of
, 4-difluoro-2-(1-mesyloxyisopropoxy)aniline in 30 mβ of toluene with 1.7 g of powdered potassium hydroxide, 1.0 g of powdered potassium carbonate and 0
．． 2 g of tetrabutylammonium hydrogen sulfate was added to the stirred mixture. The temperature did not rise above 30'C. After stirring the mixture overnight at room temperature, water was added and the organic layer was separated and washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude residue was purified by chromatography on silica gel (developing solution: toluene),
Obtained 0.2 g of oily title product. This is [α) =-
It was 40.0° (c=0.45, CHCf3).

Yield: I6.9%.

1HNMl? (CDC13)ppI11) Delta=1.
42(d, 38).

3.08 and 3.35 (dABq, 2)1), 3
．． 7 (br, s, IH).

4.26 (m, IH), 6.26 (m, IH)
, 6.53 (m, 1B).

A solution of 2.6 g of diethyl azodicarboxylate in dry tetrahydrofuran at 50 mA, 2.5 g of 2-chloro-3-fluoro-6-nitrophenol, 4.91 g of (S)-1 in dry tetrahydrofuran at 50 mA
-(4,4'-Dimethoxytrityloxy)-2-propanol and 3.95 g of triphenylphosphine were added slowly to a stirred solution. The mixture was then stirred at room temperature for 18 hours.

This was then concentrated under reduced pressure and the residue was treated with a mixture of diethyl ether and hexane and filtered. The filtrate was washed with 2N hydroxide solution and water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness.
．． 0 g of coarse lysate was obtained. Dissolve this in 100ml of methanol and add 5g of DOWEX 50W-X8-400.
H'' (RTM) ion exchange resin and stirred at room temperature for 2 hours. Next, the ion exchange resin was filtered off, and the filtrate was distilled off under reduced pressure.

The residue was purified by chromatography on silica gel (diethyl ether/hexane: 1/1), 1.9 g
of pure title product and 1.3 g of slightly impure fraction were obtained. The pure product is [α) = +10.3° (c =
1.0, CHCj! z) T near-yri.

'II NMR (CDCIl 3.ppm) delta=1
．． 33(d, 3+1).

3.80 (m, 211), 4.66 (m,
IIIL 7.04 (dd, IH).

7.81(dd, II().

3.0 g of (R)-3-chloro-4-fluoro-2-(
l-Hydroxyisopropoxy)nitrobenzene at 7 On/! as described in Example 83. Mesylation was carried out with 1.72 g of methanesulfonyl chloride and 2.8 ml of triethylamine in dry diethyl ether and work-up was carried out similarly. The residue was purified by chromatography on silica gel (developing solution Nidiethyl ether/hexane; 1/1) to give 2.6 g of the oily title product. This is (α) = -60,9° (c = 1.0, CHC
l3). Yield: 66.0%.

'HNMR (CDCl 3.ppm) delta = 1.43
(d, 3)1).

3.0Hg, 3H), 4.39(m, 2H
), 4.80 (m, IH).

7.09(dd, 11(), 7.86(dd,
xlD.

2.5 g of (R)-3-chloro-4-fluoro2- (
1-Mesyloxyisopropoxy)nitrobenzene was reduced with 0.3 g of 10% Pd/C in H2 and 70II11 absolute ethanol as described in Example 84, with similar work-up. 2.1 g of oily title product was isolated, which was [α] = +3.0° (c = 1.0, CH
Cj! i). Yield: 91%.

'HNMR (CDC13, IllIPm) delta = 1.
40(d, 3+1).

3.06 (s, 3H), 4.36 (n+, 2H
), 4.70 (s, IH).

6.57(dd, 18), 6.78(dd, 1
)1).

Fruit 11LLl xazine 1,78g (R) dissolved in 10mff1 toluene
-3-chloro-4-fluoro-2-(l-mesyloxyisopropoxy)aniline in 20IIIe of toluene with 1.4 g powdered potassium hydroxide, 0.8 g powdered potassium carbonate and 0.1 g hydrogen sulfate. It was added to the stirred mixture of ammonium and cooled to 0°C.

The mixture was stirred at the low temperature for 4 hours and left at room temperature overnight. Water was added and the organic layer was separated, washed with water and evaporated under reduced pressure. The residue was purified by silica gel chromatography using a developing solution of Nidiethyl ether/hexane: 3
/2), 1.25 g of oily title product was obtained. This is slightly impure, [α) = +38.4° (c
= 2.0, CHCj! z). Yield: 100
%.

'HNMR (CDC1x-ppm) delta = 1.42 (
d, 3H).

3.06 and 3.34 (2x dd, 28), 4
．． 30 (m, IH).

6.43 (m, III), 6.56 (m,
IH).

Trobenzene 1.04 g of 2-chloro-3-fluoro-6-nitrothiophenol in 25II+1 acetone
(S)-2,3-isopropylidenedioxy-1-)
It was mixed with siloxypropane and 3.0 g of powdered potassium carbonate and heated under reflux for 8 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between diethyl ether and water. The ether layer was separated, washed with 2N sodium hydroxide solution and water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness.

The residue was purified by chromatography on silica gel using the developing solution Nidiethyl ether/hexane (1/1), 0
．． 4 g of the oily title compound was obtained. Yield: 24.8%.

'HNMR (CDC13, ppm) delta = 1.30 (
s, 3)1).

1.36(s, 3)1), 2.96 and 3.23
(2x t*, 211).

3.72 and 4.08 (2x rn, 21(),
4.20 (m, IH), 7.28 (m, 1
8), 7.59 (m, 1) 1).

Example 91 A solution of 3.83 g of diethyl azodicarboxylate in 10 ml of tetrahydrofuran was dissolved in 60 ml of tetrahydrofuran while maintaining the temperature at 20°C.
2-chloro-3-fluoro-6-nitrophenol, 1.52 g of (S)-1°2-propanediol, and 5.76 g of triphenylphosphine were added slowly to a stirred solution. The mixture was stirred overnight at room temperature. Thereafter, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between diethyl ether and water. The solid material was filtered off and the ether layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (developing solution Nidiethyl ether/hexane: 2/3) to obtain 3.4 g of an oily product consisting of a 3:1 mixture of the title compound. The mixture is [α]
-+7.8' (c=1.3, CHCj!, 1)
It is.

'HNMR (CDCl 3.E) 9111) subcompound,
Delta = 1.28 (d, 3) 1), 4.07 and 4.20 (dABq, 2H), 4.28 (m, 1
B), 7.12 (m, IH), 7.87 (m
, IH), main compound, delta = 1.33 (d,
3) 1), 3.80 (m, 2B).

4.66 (m, IH), 7.07 (m, 1
ll), 7.82 (m, IH).

0.94 g of (R)-2-(2-(1-ethoxyethoxy)propoxy)-3,4-difluoronitrobenzene was dissolved in 1011 Il of methanol.

0.3 g of 10% Pd/C and 1.5 g of ammonium formate were added and the mixture was stirred vigorously. The temperature is 3
The temperature did not rise above 5°C. The mixture was stirred for 0.5 hours and then filtered through Hyflo (RTM). The filtrate was evaporated to dryness and the residue was partitioned between water and diethyl ether.

The ether layer was separated, washed once with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by chromatography on silica gel (developing solution: Nidiethyl ether/hexane: 3/2) to obtain 0.8 g of the title compound. Yield: 94.0%.

'HNMR (CDC1s, ppm) delta = 1.22
(m, 3H).

1.30 (d, 3H), 1.35 (6,38),
3.53-3.66 (m.

2H), 3.96-4.13(m, 3H), 4
．． 86(m, II(), 6.36(m, 1)1)
, 6.69 (m, 1)1).

Example 93 After cooling a stirred suspension of 6.72 g of powdered potassium hydroxide and 4.14 g of powdered potassium carbonate in 80 ml of toluene to -5°C, 45 mj! in toluene of 5.3
) g of 2.3.4-)lifluoronitrobenzene and 5.18 g of (R)-2-(1-ethoxyethoxy)
A solution of -1-propanol was slowly added while maintaining the temperature at 0<0>C. Next, the mixture was stirred for 0.5 hours.
Water was added and the organic phase was separated. The aqueous layer was extracted twice with toluene, and the combined organic layers were washed several times with water until pH=8. The organic phase was evaporated to dryness and the residue was purified by chromatography on silica gel.Developing solution: hexane/diethyl ether/triethylamine: 2/L 10.0
1), 8.0 g of the title compound, a 1:1 mixture of diastereomers, was obtained. Yield: 87%.

'HNMR (CDC13-ppm) delta = 1.18
(tr, 3)1).

1.21 (tr, 3H), 1.30 (m, 6)
0. 3.58 (m, 2B).

4.1-4.4 (o+, 3H), 4.82 (q,
1) 1), 4.86 (q.

III), 7.00 (m, IH), 7.66
(m, IH).

An additional 0.7 g of a more polar by-product was obtained, identified as (R,R)-,2,4-bis[2-(1-ethoxyethoxy)propoxy]-3-fluoronitrobenzene. Yield: 6.7%.

'HNMR (CDC13+ ppn+) delta=1.2
0 (m, 6H).

1.33 (n+, 12fl), 3.52 and 3
．． 68 (2x tm, 4H).

4.01-4.16 (m, 68), 4.86 (m
, 21), 6.79 (m.

In), 7.71 (m, IH).

A mixture of 0.84 g (S)-1,2-propanediol and 0.25 g lithium amide in dry tetrahydrofuran was stirred at room temperature for 1 hour.
j! to tetrahydrofuran? Capacity 1, 77g 2
．． 3.4-) Gradually add refluoronitrobenzene,
The reaction mixture was then stirred for 1 hour. The mixture was concentrated under reduced pressure and the residue was partitioned between diethyl ether and water. The ether layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography to obtain 1.2 g of a 63:37 mixture of physical compounds (developing solution: hexane/diethyl ether: 3/2). Yield: 51.5%.

The mixture has (α) = -30,4° (C = 2.3,
CHCJ2).

'HNMR (CDCl z, ppm) delta = 1.26
(d, 3)1).

4.11 and 4.36 (2x m, 2tl), 4
．． 26 (m, III).

7.01 (m, IH), 77-71 (+ 1tl
).

Sub-compound: delta = 1.40 (d, 30), 3.78
(m, 2H).

4.70 (n+, IH), 7.01 (m,
III), 7.71 (m, 1B).

Additionally, 0.15 g of by-product was isolated. Its structure was determined to be (S)-1,2-bis(2,3-difluoro-6-nitrophenoxy)propane. Yield: 8.0
%.

'II NMR(CDCl 3.fI)m) delta=1
．． 53(d, 3H).

4.36 and 4.60 (2x m, 211), 5
．． 00(m, 11().

6.99 (m, 2H), 7.66 (m, 21
1).

After washing 0.5 g of 60% sodium hydride with pentane, 12.5+j! of dry tetrahydrofuran. The suspension was stirred, cooled to 10°C, and 9 rml
3.8 g of (S)-1,2 in dry tetrahydrofuran
- Added propanediol. The mixture was stirred for 0.5 hour. 10ml of the solution was heated to 10ml while keeping it at 10°C.
j! of 0.97 g of 3-chloro-
Then, the reaction mixture was stirred for 0.5 hour and concentrated under reduced pressure. The residue was treated with water and diethyl ether.

The ether layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness.

The crude product was purified by chromatography on silica gel (developing solution Nidiethyl ether/hexane: 1/1).
, 0.8 g of a 65:35 mixture of the title compound was obtained. Yield: 65%.

'HNMR (CDCl ff+ ppm) Main compound, delta = 1.28 (d, 3H), 4.07 and 4.
20 (2x dd, 18).

4.27 (m, 1ll), 7.08 (m, Hl
), 7.86 (m, LH).

Regioisomer, delta = 1.34 (d, 3H).

3.79 (m, 2H), 4.66 (+m+ 18
), 7.08 (+++, III).

7.86 (+w, 1B).

The same ratio of regioisomers was obtained by carrying out the reaction in dimethyl sulfoxide.

1OL117! of 1.77 g of 2 in diethyl ether
゜3.4-trifluoronitrobenzene and 0.76g
ml of (S)-1,2-propanediol at 30°C while keeping the temperature at -10°C! 2. in toluene.
Mixed dropwise into a stirred suspension of 24 g of powdered potassium hydroxide and 1.38 g of powdered potassium carbonate. The mixture was then stirred at the low temperature for 0.5 hours.

Water was added to the mixture, and the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.

The residue was purified by chromatography on silica gel (developing solution Nidiethyl ether/hexane: 1/1).
, 1.6 g of the title compound was obtained. This is (α) =+
6). 8° (c = 1.5, CH(J,). Yield: a2.O%.

'il NMRCCDCIt + ppm) delta = 1
．． 53(d, 3+1).

4.38 and 4.60 (d[lq, 28), 4.
99 (m, IB), 7.02 (sr, 211)
, 7.67 (m, 2H).

Furthermore, (S)-3,4-difluoro-2-(2-hydroxypropoxy)nitrobenzene and (S)-3,4
-difluoro-2-(1-hydroxyisopropoxy)
0.3 g of a mixture of nitrobenzene was obtained. Yield: 1
3.3% The reaction was carried out again, but this time at 10 mj! of (S)-1,2-propanediol in tetrahydrofuran while maintaining the temperature at -10"C.
Added to a stirred suspension of 1.38 g of powdered potassium carbonate and 1.77 g of 2.3.4-trifluoronitrobenzene in 30...l of tetrahydrofuran. The suspension was then stirred for 2 hours at -10"C and worked up as described above. 1.65 g of assembled material was purified and NM
1.2 g of the title product was obtained as evidenced by .R analysis. Yield; 6). 5% and 0.1 g of a 55:45 mixture of the regioisomers described above was obtained.

'If NMR (CDCβ3). ppm) delta=1
．． 26(d, 3+1).

4.13 and 4.37 (dABq, 2H), 4.
26 (m, III), 7.02 (a+, III
), 7.70 (m, III).

Regioisomer, delta = 1.40 (d, 3H).

3.78 (m, 28), 4.70 (m, IH)
, 7.02 (m, l1l).

7.70 (m, IH).

The mixture was developed with a ratio of 1/1 to obtain 3.3 g of the title compound as an oil. Yield: 85%. The product is [α) = +57.5°(
c = 1.9, CHCl,).

'It NMR (CDCI 3) ppm) delta=1.
53(d, 3)1).

4.38 and 4.60 (dABq, 211), 4
．． 98 (m, 1)ri, 7.02 (m, 2H),
7.67 (m, 211).

A solution of 2.09 g of diethyl azodicarboxylate in 10 Il of tetrahydrofuran was heated to a temperature of 20°C.
2.3 in 40 ml of tetrahydrofuran while maintaining
3 g of not completely pure (R)-3°4-difluoro-2-(2-hydroxypropoxy)nitrobenzene, 1.75 g of 2,3-difluoro-6-nitrophenol and 3.14 g of triphenyl Add slowly to the stirred solution of phosphine.

The mixture was stirred at room temperature for 18 hours and then worked up as described in Example 24.

Silica gel column diethyl ether/hexa 50mj
2 in tetrahydrofuran at 10. 'A solution of 4 g of diethyl azodicarboxylate was dissolved in 9.6 g of 2-chloro-3-fluoro-6 in 250 ml of tetrahydrofuran.
-nitrophenol, 8.0 g of (S)-2-(2-tetrahydropyranyloxy)-1-propanol and 1
Add slowly to a stirred solution of 5.7 g of triphenylphosphine. After stirring the reaction mixture overnight, Example 24
Post-processing was performed as described in . Purification by chromatography on silica gel (developing solution: hexane/diethyl ether/triethylamine: 3/210.025)
16. as a 2:1 mixture of both diastereomers.
Obtained 0 g of the title compound. The mixture is [α) =-
29.7° (c = 2.2, CHCffiz), yield; 96%.

'HNMR (CDCβ3) ppn+) delta = 1.3
8(d, 3H).

1.5-1.9 (m, 6B), 3.52 and 3.
91 (2x ra, 28).

4.1-4.3 (m, 3H), 4.86 (tr,
IH), 7.07 (m.

1) 1), 7.84 (m+IH).

Subcompound, delta = 1.33 (d, 3H), 1.
5-1.9 (m.

6H), 3.52 and 3.91 (2x ta, 2
11), 4.1-4.3 (m.

3H), 4.78(tr, 1tl), 7.07(
n+, 1ll), 7.84 (m, 111).

5.8 g of 3-chloro-2°4- in 20 ml of toluene
A solution of difluoronitrobenzene was added with 5.6 g of powdered potassium hydroxide, 4.55 g, while maintaining the temperature at 15°C.
g of powdered potassium carbonate and 5.3 g of (S)-2-(
2-Tetrahydropyranyloxy)-1-propanol was slowly added to the stirred suspension. The reaction mixture was heated to 0 at room temperature.
．． Stirred for 5 hours. Water was added and the organic layer was separated. The aqueous layer was extracted once with toluene. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure.
g of coarse material was obtained. This was purified by chromatography on silica gel (developing solution: Nidiethyl ether/hexane: 1/1) to obtain 6.8 g of the title compound. According to TLC analysis, this was comparable to the product obtained in Example 33. Yield: 68%.

In addition, 2.7 g of a by-product and 0.5 g of a second by-product were obtained, which were determined by NMR analysis to be diastereomeric (S,5)-3-chloro-2,4-bis(2-(2-tetrahydropyrani). The diastereomers were not completely separated. Yield: 29.1%.

'HNMR (CDCl x, ppm) delta = 1.3)
and 1.38 (2x d, 6fl), 1.4-1
．． 9 (m+128), 3.52 (m, 2H).

3.9-4.3 (m, 811), 4.81 and 4
．． 90 (2x m, 211).

6.84 (d, 111), 7.89 (d,
il+).

Diastereomer, delta = 1.36 and 1,38
(2xd, 6)1), 1.4-1.9(m, 6
)1), 3.53 (m, 211).

3.9-4.4 (m, 811), 4.90 and 4
．． 95 (2x m, 2H).

6.78 (d, LH), 7.88 (d, 18)
.

In previous experiments, catalytic amounts of tetrabutylammonium hydrogen sulfate were used. The title compound was obtained in 65% yield, with approximately the same amount of by-products formed above.

In subsequent experiments, a mixture of 2.3.4-)lifluoronitrobenzene and (S)-2-(2-tetrahydropyranyloxy)-1-propanol in toluene was mixed with powdered potassium hydroxide and powdered potassium carbonate in toluene. Added to the mixture. After purification, the title compound was obtained in 84% yield.

By-products were clearly smaller.

(2-Tetrahydropyranyloxy)propoxy] 0.96 g in 5 ml dry dimethylformamide
2-chloro-3-fluoro-6-nitrophenol,
1.05g ethyldiisopropylamine and 1.48g
A mixture of (R)-1-iodo-2-(2-tetrahydropyranyloxy)propane of 80-100 g was stirred.
Heated at ℃ for 30 hours. The reaction mixture was cooled and evaporated under reduced pressure. The residue was diluted with toluene, and the solvent was distilled off under reduced pressure.

The residue was partitioned between diethyl ether and water. The ether layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The cough granules were purified by chromatography on silica gel, eluent Nidiethyl ether/hexane: 1/4 and 0.5% triethylamine), as a 5:2 mixture of diastereomers.
The title compound of g was obtained. The NMR spectrum is that of Example 9.
The results were similar to those reported in 8.

In a previous experiment, 2 in 8 ml dimethylformamide
．． 2 g of potassium 2-chloro-3-fluoro-6-nitrofuninoxide and 2.7 g of (R)-1-iodo-
8 2-(2-tetrahydropyranyloxy)propane
Heated at 0-100°C for 36 hours. Work-up was similar to that described above. After purification, 0.9 g of oil was obtained, 40% of which consisted of the title compound as a mixture of diastereomers, as evidenced by NMR analysis.

Example 101 0.53 g of powdered potassium hydroxide were added to a solution of 1.9 g of 2-chloro-3-fluoro-6-nitrophenol in 70+nj' dimethylformamide and the mixture was stirred for 1 hour. 1.4 g of (S)-1-bromo-2
-Add propanol and stir the mixture until 80-
Heated at 100°C for 16 hours.

Thereafter, the reaction mixture was concentrated under reduced pressure, and water and diethyl ether were added to the residue. The ether layer was separated and 0.
Washed with IN sodium hydroxide solution and water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1
．． 2 g of product was obtained, which was purified by chromatography on silica gel (developing solution: hexane/diethyl ether: 1/1).

0.9 g of a 2=1 mixture of the title compound was obtained. yield:
37.5%, the mixture has [α) = +6.9° (c =
2.13, CHI 13), the main compound consisted of a 94:6 mixture of optical isomers.

11 NMR (CD (J * ppm) delta = 1.2
8(d, 3+1).

4.08 and 4.21 (dABq, 2H), 4.
28(n+, 111).

7.09 (m, III), 7.87 (m, II
I).

Subcompound, delta-1,35(d, 3H), 3.8
0 (+w, 211).

4.66 (m, 1) 1), 7.06 (m, IH
), 7.82 (m, 1ll).

15.0 g of (S)-3-chloro-4-fluoro-2
-(2-(2-Tetrahydropyranyloxy)propoxyconitrobenzene was dissolved in 200ml of methanol. 15II11 of 4N hydrochloric acid was added.

After stirring at room temperature for 0.5 h, TLC analysis (hexane/
Diethyl ether: 90% of the starting material was hydrolyzed as shown by 1/1). Another 5 mj! of 4N hydrochloric acid was added and stirring continued for 0.5 hour. After neutralizing the reaction mixture by adding 2N sodium hydroxide solution, the solution was evaporated to dryness. The residue was partitioned between diethyl ether and water. Separate the organic layer, wash with water and dilute with anhydrous sulfuric acid)
Dry over IJum, filter and evaporate to dryness. 11.9
g was obtained, which was purified by chromatography on silica gel (developing solution Nidiethyl ether/hexane: 1/1) to obtain 9.8 g of an oily product consisting of a 2:1 mixture of the title compound. Yield: 87.5%.

'HNMR (CDC1:l, ppm) Main compound, delta = 1.27 (d, 3) 1), 4.13 (dABq
, 211), 4.26 (m, 1B).

7, IHdd, IH), 7.87(dd, II
I).

Regioisomer, delta = 1.34 (d, 3H).

3.78 (d, 21), 4.63 (m, I
H), 7.06 (m, 18).

7, a2 (dd, l1l).

In 15 ml of methanol, (α) = +4.1° (c
After adding 1.0+nl of 4N hydrochloric acid to a stirred solution of 1.0 g of (R)-3,4-difluoro-2-(2-hydroxypropoxy)nitrobenzene (=2.0, CHCl1x), the mixed solution was stirred for 0.5 hour.

Add 2N sodium hydroxide solution to the mixture to neutralize it,
It was concentrated under reduced pressure. The residue was dissolved in diethyl ether and the ether layer was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness.

NMR analysis showed the product to be a 2:1 mixture of the title isomers. The mixture is [α) = +27
．． 1° (c = 2.0, CHCA3),
This value confirmed the (R)-configuration of both isomers.

'HNMR (CDCj!!, ppm) delta = 1.
26(d, 3)1).

4.11 and 4.39 (dABq, 2fl), 4
．． 23 (a+, IH), 7.00 (Peng, IH)
, 7.73(s, IH).

Regioisomer, delta = 1.40 (d, 3) 1)
.

3.79 (m, 2H), 4.70 (n+, II
I), 7.00 (o+, 111).

7.67 (cap 111).

Complete conversion was demonstrated. The reaction mixture was evaporated to dryness and the residue was partitioned between diethyl ether and water. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate,
Concentration under reduced pressure gave 5.6 g of a 2:1 mixture of the title compound. The compound was used as is in Example 105. yield:
94.8%.

4.5 g of the mixture obtained in Example 102 and 3.7 l of steel
of triethylamine was dissolved in 8011 Il of dry tetrahydrofuran. The mixture was stirred and a solution of 2.29 g of methanesulfonyl chloride in 25 III l of dry tetrahydrofuran was added while maintaining the temperature at 10.degree. TLC analysis of silica gel (developing solution: petroleum ether (
40-60)/diethyl ether: 1/1), immediately after the end of the addition, the mixture prepared in Example 104 5.6
G to 15mj! of dry acetone. 1 of the solution
7.4 g of lithium bromide in 00 ml of acetone and 10
0 ml of cupric bromide was gradually added to the stirred mixture. The reaction mixture was heated under reflux for 24 hours and evaporated to dryness. The residue was partitioned between water and diethyl ether.

The layers were separated and the ethereal phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using the developing solution Nidiethyl ether/Petroleum ether (40-60):
2/3), 4.7 g of a 2:1 mixture of the title compound was obtained. Yield: 88.0%. Example 106 using the mixture as it is
used for.

'HNMR (CDCl *, ppM) Main compound, delta = 1.86 (d, 3tl), 4.35 (dABq
, 211), 4.42 (m, IH).

7.10 (dd, 1B), 7.86 (dd, I
H).

Subcompound, delta = 1.50 (d, 3) 1), 3
．． 59 (dABq.

211), 4.71 (m, 1B), 7.10 (
dd, IH), 7.86 (dd.

18).

4.7 g of the mixture produced in Example 105 was added to 501111
of 10% Pd/C dissolved in absolute ethanol of
added. The suspension was stirred vigorously and saturated with H2. After the required amount of H2 has been absorbed, the catalyst is heated to Hyflo (R
TM) and the filtrate was evaporated to dryness. The residue was dissolved in diethyl ether, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. 2:1 of the title compound
4.2 g of mixture was obtained. Yield: 98.9%. The mixture was used directly in Example 107.

1 while stirring 4.0 g of the mixture described in Example 106.
Dissolved in 25o+1 dry tetrahydrofuran. Add 3.8 g of potassium tert-butoxide to this solution.
The mixture was added in small portions over 20 minutes at 5°C. The reaction mixture was stirred for 1 hour and then concentrated at low temperature. The residue was partitioned between diethyl ether and water.

The ether layer was separated, washed with water until neutral pH, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 3 g of crude material. This was purified by chromatography on silica gel (developing solution: hexane/diethyl ether: 2/3).

The title compounds were obtained in yields of 1.3 g and 0.6 g, respectively. (66,6%), the latter is [α] = -38,9
° (c = 1.3, CHCffis).

TLC analysis (silica gel; hexane/diethyl ether: 1/1) showed that the recompounding was comparable to the confirmed sample.

Zen 50m1! A solution of 10.4 g of diethyl azodicarboxylate in tetrahydrofuran of
．． 55 g of 2,3-difluoro-6-nitrothiophenol, (R)-2,3-isopropylidenedioxy-
1-Propanol and 15.7 g of triphenylphosphine were added slowly to the stirred mixture. The reaction mixture was stirred at room temperature for 18 hours and then worked up as described in Example 24. A 3/1 mixture of hexane/diethyl ether was used as the developing solution for the chromatographic purification. The product fractions were combined and evaporated to dryness. The residue was treated with hexane and the remaining insoluble triphenylphosphine oxide was removed by filtration.

The filtrate was concentrated under reduced pressure, [α) = +34.7° (c =
8.35 g of the oily title compound (1,5,CHCl,) was obtained. Yield: 54%.

'II NMR (CDCI!, ppm) delta =
1.30(s, 3)1).

1.35(s, 3)(), 3.05 and 3.30
(dABq, 2+1), 3.73 and 4.06(d
ABq, 2H), 4.21 (m+ 1il),
7.24 (o+.

IH), 7.69 (m, IB).

5.4 g of (S)-3,4-difluoro-2-(2,3
-isopropylidenedioxyprobylthio)nitrobenzene was dissolved in 400 sJ of methanol without stirring. 1.0g DOWEX 50W-8X-400H=
(RTM) ion exchange resin was added and the mixture was stirred at room temperature for 18 hours. The resin was filtered off, and the filtrate was concentrated under reduced pressure. The solid residue was recrystallized from diethyl ether/pentane, [α] = +24. O° (C=1.0, CH
3.7 g of the title compound of CIt 3) were obtained. M, p, 7
0-71℃. Yield near 8%.

'HNMR (CDC1s + DMSO (06), p
pm) Delta = 3.54 (m, 2H>, 3.63
and 3.76 (2x m, 2H), 3.96<m,
1N), 7.24 (m, LH), 7.69 (
m, 1)1).

Example 110 2.5 g of ammonium formate was dissolved in 1.56 g of (R)-3,4- in 5 ml of methanol with vigorous stirring.
Added to a solution of difluoro-2-(2-mesyloxypropoxy)nitrobenzene and 0.5 g of 10% Pd/C. The reaction mixture was stirred at room temperature for 2 hours and then heated with Hyflo (RT
Filtered with M>. The filtrate was concentrated under reduced pressure. The residue was partitioned between water and diethyl ether. separating the ether layer;
The aqueous layer was extracted twice with diethyl ether. The combined ether fractions were washed with water, dried over anhydrous sulfur sulfate, filtered and evaporated under reduced pressure to yield 1.45 g of the title compound as an oil contaminated with 10 mol% solvent.

'II NMR (CDCI!3.ppm) delta=1
．． 48(d, 3+1).

3.10 (s, 38), 4.14 (m, 211)
), 5.13 (m, 1tl).

6.39 (m, 1ll), 6.71 (q, III
).

Pre-washed 60% sodium hydride 0.
Mix 4g with 20mj2 of diethyl ether and add 10m
2.33 g of (R)-3,4 in 1 part diethyl ether
-difluoro-2-(2-hydroxypropoxy)nitrobenzene was added with stirring. After stirring the mixture for 0.5 h, IO ml of diethyl ether April, 9
Gradually add g of p-)luenesulfonyl chloride;
Stirring was continued for 18 hours at room temperature and for a further 6 hours at reflux temperature. The reaction mixture was cooled, water was added and the ether layer was separated, washed with water, dried over anhydrous sulfuric acid, filtered and evaporated to dryness. The residue was purified by silica gel chromatography to obtain 2.0 g of a 5:l mixture of a class a compound and its regioisomer (developing solution: hexane/diethyl ether: 1/l). Yield: 51
．． 7%. The mixture solidifies while standing, and [α]
=-16.5° (c=0.75, CHC13). The mixture was recrystallized from diethyl ether/pentane, [α] = -23,3° (c=C03,
CHCj'3) and m, p, 62-63°C were obtained.

IHNMR (CDCj73.I)13m) Delta = 1
．． 40(d, 3H).

2.45 (s, 3H), 4.20 (m, 2H)
, 4.75 (m, LH>.

6.99 (m, IH), 7.33 and 7.73
(ABq, 4H), 7.66 (m, IH).

Regioisomer, delta = 1.44 (d, 3) 1)
.

2.41 (s, 3H), 4.20 (m, 2H)
, 4.93 (m, LH).

6.99 (m, IH), 7.29 and 7.80
(ABq, 4H), 7.66(+n, IH
).

The mixture was used directly in Example 112.

1. LILI 1.7 g of the mixture prepared in Example 111 was dissolved in 40 ml of absolute ethanol, and 0.4 g of 10%
Pd/C was added. Stir the mixture vigorously and add H2
saturated with. After the required amount of H2 was absorbed, the catalyst was filtered off with Hyflo (RTM) and the filtrate was concentrated to dryness. The residue was dissolved in diethyl ether and the ethanol layer was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give 5.2 of the title compound and its regioisomer.
1.4 g of a 5:1 mixture was obtained. Yield: 100%. The mixture has [α) = −12,4° (c=1.0, CH
Clz).

'HNMR(CD(1,,ppm)delta=1,3Hd
, 3) 1).

2.43 (s, 3B), 3.66 (br, s, 2
H), 4.14 (m, 28).

4.43 (+*, LH), 6.36 (m, LH
), 6.69 (m, LH).

7.33 and 7.78 (ABq, 41().

Regioisomer, delta = 1.35 (d, 3+1)
.

2.43 (s, 38), 3.66 (br, s,
2H), 4.14 (m, 2H).

4.95 (m, IH), 6.36 (m, 1
ll), 6.69 (m, LH).

7.33 and 7.78 (ABq, 411).

The mixture was used directly in Example 113.

This was comparable to the sample confirmed by TLC and IR. The compound has [α] =435, 6°
(c=1.5, CHCl3). Yield: 80.
0%.

'HNMR (CDC13, ppn+) delta = 1.41
(d, 3H).

3.08 and 3.34 (dABq, 2H), 4.2
7 (m, IH), 6.26 (m, IH),
6.54 (m, III).

1.2 g of the mixture prepared in Example 112 was dissolved in 51I11 toluene and the resulting solution was mixed with 0.7 g of powdered potassium hydroxide, 0.4 g of powdered potassium hydroxide in 15 nl of toluene, maintaining the temperature at 5 °C. Powdered potassium carbonate and 50 μm of tetrabutylammonium hydrogen sulfate were gradually added to the crystallized solution with stirring. The reaction mixture was heated at 5°C for 1 hour and at room temperature for 1 hour.
and stirred at 40°C for 4 hours. Finally, the reaction mixture was left overnight.

Water was added, and the organic layer was washed with separated water and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (developing solution: hexane/diethyl ether: 1/1),
0.5 g of the title compound was obtained.

0.4 g of 60% sodium hydride, previously washed with pentane, was suspended in 20 ml of dry diethyl ether with stirring, and 2.33 g of (R)-3,4-difluoro-2-(2-hydroxypropoxy ) nitrobenzene was added. The mixture was heated at reflux temperature for 2 hours.

The reaction mixture was cooled, water was added and the organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated to dryness.
α] = +38°1° (c = 2.0, CHClf
2.2 g of a mixture of the title compound of f) was obtained.

Isomerization is achieved by heating the diethyl ether mixture under reflux for 4 hours! Continued 3. After post-processing by the above method, [α] = +
3 5. A mixture of 7° (c=2.0, CHCl3) was obtained.

Purified by chromatography, developing solution Nidiethyl ether/hexane: 9/1), Cα]=+16.3@
(c=2.0, C HC f ,) of the title compound 1.
5g was obtained. Yield near 5%.

'H NMR (C[lC1s.ppm) delta=
3.52 (m, 18).

3, 62 and 3.72 (dABq. 2) 1), 4
．． 09 and 4. 24 (dABq.

2H), 6.29 (m.ltl), 6.56
(m. IH).

dioxazine 3,5 5 g of (R)-7,8-difluoro-2.

Claims (1)

[Claims] (1) (R)- or (S)-7-fluoro-8-X-3,4-dihydro-2H-[1,4]benzoxazine and -benzothiazine of general formula III , chemical formulas, tables, etc.▼...III (In the formula, one of the substituents R^1, R^2, R^3, and R^4 represents CH_2OH or CH_2Z, and the others represent hydrogen. .Z represents hydrogen, fluorine or a protected hydroxyl group, Y represents oxygen or sulfur, X represents fluorine, chlorine, methyl group or hydrogen, provided that R^
For benzoxazines in which both 3 and R^4 represent hydrogen, X represents a methyl group or hydrogen). (2) (R)- or (S)-pyridobenzothiazine of general formula But, Q^
1 and Q^2 are the same or different and represent either hydrogen or a (1-6C) alkyl group (however, Q
^1 and Q^2 do not both represent hydrogen), or both contain one or two nitrogen ring atoms and/or one oxygen ring atom, It forms a (3-7C) heterocycle which may be substituted by groups. Also, R^1, R^2, R^3, R^
4 and X are defined in claim (1)). (3) 7-Fluoro-8-X-3,4- of general formula III in stereochemically pure form or as a racemic mixture
Dihydro-2H-[1,4]benzoxazine and -benzothiazine▲Mathematical formulas, chemical formulas, tables, etc.▼...III (In the formula, X represents fluorine, chlorine, methyl group, or hydrogen, and Y represents oxygen or Indicates sulfur. Also, in a, raw material compound IX, R^6 = hydroxyl group and R^5
= In the case of hydrogen, R^1 = CH_2Z or CH_2O
H, or b, in the starting compound IX, R^6=hydrogen and R^5=
In the case of hydroxyl group, R^2=CH_2Z or CH_2O
H, or c, in the starting compound X, R^7=hydrogen and R^8=
In the case of methyl hydroxide, R^3=CH_2Z or CH
_2OH, or d, in the raw material compound X, when R^7 = methyl hydroxide and R^3 = hydrogen, R^4 = CH_2Z or CH
_2OH, and in any case, the other R represents hydrogen,
4-fluoro-3-halo of formula IX in stereochemically pure form or as a racemic mixture. -2-(hydroxy(3c)alkyl-Y)
) Nitrobenzene▲There are mathematical formulas, chemical formulas, tables, etc.▼...(IX) (In the formula, R^5 = hydroxyl group and R^6 = hydrogen, or R
Either ^5 = hydrogen and R^6 = hydroxyl group, and X
^1 represents fluorine or chlorine, Y represents oxygen or sulfur, and Z represents what is defined in claim (1))
, and/or 4-fluoro-3-halo-2-( of formula X in stereochemically pure form or as a racemic mixture)
Hydroxy (3c) alkyl-Y) nitrobenzene ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼...X (In the formula, R^7 = hydrogen and R^8 = methyl hydroxide, or R^7 = methyl hydroxide and R^8=hydrogen, and X^1, Y and Z are as defined for formula IX above) with a hydroxyl group activator, the hydroxyl group is removed by a suitable leaving group. reaction step b to obtain the corresponding compound of formula IXa or Xa which is substituted and the other substituents are as previously defined. IX, IXa using reducing agent
, a step of obtaining an aniline derivative by converting the nitro group of X or Xa into an amino group; c. a step of ring-closing the obtained aniline derivative by treating the obtained aniline derivative with a base; d. of the 8-fluorine atom of the ring-closed aniline derivative,
An optional substitution step with a methyl group or a hydrogen atom by a method known in the art; e. An optional removal step of the hydroxyl protecting group of CH_2Z of the obtained ring-closed aniline derivative by a method known in the art. (4) In the method according to claim (3), the leaving group calitylsulfonyloxy group, p-toluenesulfonyloxy group, bromine atom or (phenyl), a group represented by the formula P^+-O- A method characterized in that the group is selected from the group comprising: (5) The method according to claim (3) or (4), wherein the reducing agent is selected from the group including Raney nickel, stannous chloride, metallic tin and hydrogen, or ammonium formate in combination with a noble metal catalyst. How to do it. (6) The method according to any one of claims (3) to (5), wherein the base that brings about ring closure is potassium tert.
- a process characterized in that it is butoxide, potassium hydroxide or, preferably, a mixture of potassium hydroxide and potassium carbonate. (7) The method according to any one of claims (3) to (6), wherein the starting compound is 4-fluoro-3-halo-2-(hydroxy(3c
) alkyl-Y) nitrobenzene or a mixture of IX and A method characterized in that it is produced by reacting with a compound of the group containing 2-propanethiol and 2-hydroxy-3-Z-1-propanethiol (wherein Y and Z are defined in claim (3)). (halo indicates fluorine or chlorine). (8) The method according to any one of claims (3) to (6), wherein the starting compound is 4-fluoro-3-halo-2-(hydroxy(3c
) alkyl-Y) nitrobenzene or a mixture of IX and
Nitrophenol or the corresponding thiophenol,
A method characterized in that it is produced by reacting with 2-CH_2Z-oxirane of formula X I ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼... and Z are defined in claim (3)). (9) The method according to any one of claims (3) to (6), wherein the starting compound is 4-fluoro-3-halo-2-(hydroxy(3c
) alkyl-Y) nitrobenzene, or a mixture of IX and
- A method characterized in that it is produced by reacting nitrophenol or the corresponding thiophenol with 1-L-3-Z-2-propanol (L represents an atom or group that is easily eliminated, Y and Z are claims (
3), and halo represents fluorine or chlorine). (10) The method according to any one of claims (3) to (6), wherein the starting compound is 4-fluoro-3-halo-2-(hydroxy(3
c) alkyl-Y) nitrobenzene, or IX and X
A mixture of triphenylphosphine and di(1-6c
) prepared by reacting a mixture of 3-fluoro-2-halo-6-nitrophenol or the corresponding thiophenol with 3-Z-1,2-propanediol in the presence of an alkyl azodicarboxylate. A characterized method (where Y and Z are as defined in claim (3), and halo represents fluorine or chlorine)
. (11) The method according to any one of claims (3) to (6), wherein the starting compound is 4-fluoro-3-halo-2-(hydroxy(3c )alkyl-Y)nitrobenzene in the presence of triphenylphosphine and di(1-6c)alkyl azodicarboxylate to form 3-fluoro-2-halo-6
- reacting nitrophenol or the corresponding thiophenol with 2-OR''-3-Z-propanol or 1-OR''-3-Z-2-propanol, respectively, and removing the R''-group from the resulting product; (However, R'' represents a hydroxyl protecting group, halo represents fluorine or chlorine, and Y and Z are as defined in claim (3).) (2 ) The method according to any one of claims (3) to (6), wherein the starting compound is 4-fluoro-3-halo-2-(hydroxy(3c)alkyl) represented by formula IX or X, respectively. -Y) Nitrobenzene reacts with 1-L of 3-fluoro-2-halo-6-nitrophenol or the corresponding thiophenol in the presence of a base, respectively.
-2-OR″-3-Z-propane or 2-L-1-
A process characterized in that it is produced by reacting with OR''-3-Z-propane and removing the R''- group from the resulting product, where L represents a facile leaving group and R'' represents a hydroxyl protecting group, halo represents fluorine or chlorine,
Y and Z are defined in claim (3). ) (13) The method according to any one of claims (3) to (6), wherein the raw material compound 4-fluoro-3-halo-2-(hydroxy( 3c) Alkyl-Y) nitrobenzene converts 2,4-difluoro-3-halo-nitrobenzene under basic conditions into 2-OR″-3-Z-propanol or 1-OR″-3-Z-2-, respectively. A method characterized in that the product is produced by reacting with propanol or a corresponding thiol and removing the hydroxyl protecting group from the resulting product (wherein Y and Z are as defined in claim (3)). , halo represents fluorine or chlorine, R
(14) The method according to claims (3) to (13), characterized in that the asymmetric starting compound is used in a stereochemically pure form. (15) The method according to claim (14), wherein the stereochemically pure benzoxazine or benzothiazine of formula III is converted into a stereochemically pure benzoxazine or benzothiazine of the corresponding general formula XII by a method known in the art. ▲Mathematical formulas, chemical formulas, tables, etc.▼...XII (wherein A is defined in claim (2)) (16) The method according to claim (15), characterized by the following steps: a. The benzoxazine or benzothiazine is di(
1-6c) Reacting with alkyl ethoxymethylene malonate, b. Adding an acid to close the pyridine ring, c. The resulting pyridobenzoxazine or pyridobenzothiazine of formula XIV▲mathematical formula, chemical formula , tables, etc. ▼...XIV (In the formula, R^1^2 represents a (1-6c) alkyl group,
X, Y, R^1 and R^2 are as defined in claim 4) to obtain the corresponding carboxylic acid; d. optionally carrying out one of the following reactions: Subsequent step d1, reaction of replacing the 10-fluorine atom with amine NHQ^1Q^2, d2, oxidizing 10-chloro-pyridobenzothiazine to obtain the corresponding sulfoxide or sulfone, and replacing the 10-fluorine atom with the amine NHQ^1Q^2; A reaction in which the sulfoxide or sulfone is reduced to sulfide after substituting an elementary atom with an amine NHQ^1Q^2 (provided that Q^1 and Q^2 are as defined in claim (15)). (17) In the method according to claim (15) or (16), the compound represented by formula IV ▲ has a mathematical formula, chemical formula, table, etc. ▼...IV ((s)-ofloxacin) is stereochemically pure Formula X
A process characterized in that it is produced starting from a benzoxazine represented by III. ▲There are mathematical formulas, chemical formulas, tables, etc.▼... to the stereochemically pure pyridobenzoxazine or pyridobenzothiazine represented by the corresponding general formula VIII. A represents what is defined in claim (2), one of the substituents R^3 and R^4 represents CH_2OH or CH_2Z, and the other represents hydrogen. ). (19) The method according to claim (18), characterized by the following steps: a. The benzoxazine or benzothiazine is di(
1-6c) Reacting with alkyl ethoxymethylene malonate, b. Adding an acid to close the pyridine ring, c. The resulting pyridobenzoxazine or pyridobenzothiazine of formula XV ▲ mathematical formula, chemical formula , tables, etc. ▼...XV (In the formula, R^1^2 represents a (1-6c) alkyl group,
X, Y, R^3 and R^4 are as defined in claim (18)) to obtain the corresponding carboxylic acid, d. optionally one of the following reactions: d1. Reaction of replacing the 10-fluorine atom with the amine NHQ^1Q^2; d2. Oxidizing the 10-chloro-pyridobenzothiazine to obtain the corresponding sulfoxide or sulfone; 10 - A reaction in which the sulfoxide or sulfone is reduced to sulfide after replacing the chlorine atom with the amine NHQ^1Q^2 (where Q^1 and Q^2 are as defined in claim (18)). (20) Pyridobenzoxazines of general formula V with at least one therapeutically active ▲ mathematical formula, chemical formula, table, etc. ▼...V (wherein A, R^1, R^2, R^ 3 and R^4 are defined in claims (15) and (18),
The compound is in stereochemically pure form) and its pharmaceutically acceptable hydrate, salt or ester.
19) A composition produced by any one of 19). (21) Pyridobenzothiazine of general formula ▼...XVIII (wherein A, R^1, R^2, R^3 or R^4 is as defined in claim (19)) and a pharmaceutically acceptable hydrate thereof, A composition characterized in that it is a salt or an ester. (22) A pharmaceutical composition comprising (S)-ofloxacin in stereochemically pure form and one or more adjuvants or diluents, wherein (S)-ofloxacin is
5), (16) or (17). (23) one or more adjuvants or diluents, and (S)
-9-fluoro-3-methyl-10-(4-methyl-1
-piperazinyl)-7-oxo-2,3-dihydro-7
A pharmaceutical antibacterial composition containing H-pyrido[1,2,3-de][1,4]benzothiazine-6-carboxylic acid or a pharmaceutically acceptable hydrate, salt or ester thereof.